173 results on '"Ferrante RJ"'
Search Results
2. Neurochemical and histologic characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 3-nitropropionic acid
- Author
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Beal, MF, primary, Brouillet, E, additional, Jenkins, BG, additional, Ferrante, RJ, additional, Kowall, NW, additional, Miller, JM, additional, Storey, E, additional, Srivastava, R, additional, Rosen, BR, additional, and Hyman, BT, additional
- Published
- 1993
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3. Safety and tolerability of high-dosage coenzyme Q10 in Huntington's disease and healthy subjects.
- Author
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Hyson HC, Kieburtz K, Shoulson I, McDermott M, Ravina B, de Blieck EA, Cudkowicz ME, Ferrante RJ, Como P, Frank S, Zimmerman C, Ferrante K, Newhall K, Jennings D, Kelsey T, Walker F, Hunt V, Daigneault S, Goldstein M, and Weber J
- Abstract
Coenzyme Q10 (CoQ(10)), a potential neuroprotective compound, was previously investigated at a dosage of 600 mg/day in Huntington's disease (HD) patients and demonstrated a trend toward slowing disease progression. Higher CoQ(10) dosages may prove beneficial. We investigated the tolerability and blood levels associated with 1,200, 2,400, and 3,600 mg/day of CoQ(10) in HD and healthy subjects. Twenty-eight subjects (20 HD, 8 healthy) enrolled in a 20-week open-label trial. Subjects started on 1,200 mg/day of CoQ(10), increasing every 4 weeks by 1,200 mg to a maximum dosage of 3,600 mg/day. Monthly evaluations included review of adverse events and CoQ(10) blood levels. Twenty-three subjects (82%) achieved the target dosage of 3,600 mg/day. Six subjects (2 healthy, 4 HD) withdrew prematurely (gastrointestinal (GI) symptoms in 3, worsening HD in 2, and 1 because of a fall). All three serious adverse events occurred in a single subject, and were deemed unrelated to CoQ(10). The most common adverse events seen were GI symptoms. Mean (± SD) CoQ10 blood levels achieved over the course of the trial were as follows: 1.26 ± 1.27 [mu]g/mL (baseline, n = 28), 5.59 ± 2.24 [mu]g/mL (1,200 mg/day, week 4, n = 26), 6.38 ± 3.25 [mu]g/mL (2,400 mg/day, week 8, n = 25), 7.49 ± 4.09 [mu]g/mL (3,600 mg/day, week 12, n = 23), and 6.78 ± 3.36 [mu]g/mL (3,600 mg/day, week 20, n = 20). CoQ(10) was well tolerated with over 80% of subjects achieving the target dosage. Dosages of 2,400 mg/day may provide the best balance between tolerability and blood level achieved. Further studies examining the efficacy of 2,400 mg/day are planned. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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4. Proliferative and degenerative changes in striatal spiny neurons in Huntington's disease: a combined study using the section-Golgi method and calbindin D28k immunocytochemistry
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Ferrante, RJ, primary, Kowall, NW, additional, and Richardson, EP, additional
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- 1991
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5. Chronic quinolinic acid lesions in rats closely resemble Huntington's disease
- Author
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Beal, MF, primary, Ferrante, RJ, additional, Swartz, KJ, additional, and Kowall, NW, additional
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- 1991
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6. Systemic approaches to modifying quinolinic acid striatal lesions in rats
- Author
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Beal, MF, primary, Kowall, NW, additional, Swartz, KJ, additional, Ferrante, RJ, additional, and Martin, JB, additional
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- 1988
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7. Correction to "Chiral Cyclohexane 1,3-Diones as Inhibitors of Mutant SOD1-Dependent Protein Aggregation for the Treatment of ALS".
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Zhang Y, Benmohamed R, Zhang W, Kim J, Edgerly CK, Zhu Y, Morimoto RI, Ferrante RJ, Kirsch DR, and Silverman RB
- Abstract
[This corrects the article DOI: 10.1021/ml3000963.].
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- 2017
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8. Tertiary Amine Pyrazolones and Their Salts as Inhibitors of Mutant Superoxide Dismutase 1-Dependent Protein Aggregation for the Treatment of Amyotrophic Lateral Sclerosis.
- Author
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Zhang Y, Zhao KT, Fox SG, Kim J, Kirsch DR, Ferrante RJ, Morimoto RI, and Silverman RB
- Subjects
- Amines chemistry, Animals, Female, Humans, In Vitro Techniques, Male, Mice, Pyrazolones chemistry, Pyrazolones therapeutic use, Salts, Structure-Activity Relationship, Amyotrophic Lateral Sclerosis drug therapy, Pyrazolones pharmacology, Superoxide Dismutase antagonists & inhibitors
- Abstract
Pyrazolone derivatives have previously been found to be inhibitors of Cu/Zn superoxide dismutase 1 (SOD1)-dependent protein aggregation, which extended survival of an amyotrophic lateral sclerosis (ALS) mouse model. On the basis of ADME analysis, we describe herein a new series of tertiary amine-containing pyrazolones and their structure-activity relationships. Further conversion to the conjugate salts greatly improved their solubility. Phosphate compound 17 exhibited numerous benefits both to cellular activity and to CNS-related drug-like properties in vitro and in vivo, including microsomal stability, tolerated toxicity, and blood-brain barrier permeation. These results indicate that tertiary amine pyrazolones comprise a valuable class of ALS drug candidates.
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- 2015
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9. The Wnt receptor Ryk reduces neuronal and cell survival capacity by repressing FOXO activity during the early phases of mutant huntingtin pathogenicity.
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Tourette C, Farina F, Vazquez-Manrique RP, Orfila AM, Voisin J, Hernandez S, Offner N, Parker JA, Menet S, Kim J, Lyu J, Choi SH, Cormier K, Edgerly CK, Bordiuk OL, Smith K, Louise A, Halford M, Stacker S, Vert JP, Ferrante RJ, Lu W, and Neri C
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- Aged, Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins genetics, Caenorhabditis elegans Proteins metabolism, Cell Line, Female, Humans, Huntington Disease metabolism, Male, Mice, Mice, Transgenic, Middle Aged, Oligonucleotide Array Sequence Analysis, Presenilin-1 metabolism, Receptor Protein-Tyrosine Kinases genetics, Serotonin Plasma Membrane Transport Proteins genetics, Serotonin Plasma Membrane Transport Proteins metabolism, Wnt Signaling Pathway, Forkhead Transcription Factors metabolism, Huntington Disease etiology, Neurons metabolism, Receptor Protein-Tyrosine Kinases metabolism, Receptors, Wnt metabolism
- Abstract
The Wnt receptor Ryk is an evolutionary-conserved protein important during neuronal differentiation through several mechanisms, including γ-secretase cleavage and nuclear translocation of its intracellular domain (Ryk-ICD). Although the Wnt pathway may be neuroprotective, the role of Ryk in neurodegenerative disease remains unknown. We found that Ryk is up-regulated in neurons expressing mutant huntingtin (HTT) in several models of Huntington's disease (HD). Further investigation in Caenorhabditis elegans and mouse striatal cell models of HD provided a model in which the early-stage increase of Ryk promotes neuronal dysfunction by repressing the neuroprotective activity of the longevity-promoting factor FOXO through a noncanonical mechanism that implicates the Ryk-ICD fragment and its binding to the FOXO co-factor β-catenin. The Ryk-ICD fragment suppressed neuroprotection by lin-18/Ryk loss-of-function in expanded-polyQ nematodes, repressed FOXO transcriptional activity, and abolished β-catenin protection of mutant htt striatal cells against cell death vulnerability. Additionally, Ryk-ICD was increased in the nucleus of mutant htt cells, and reducing γ-secretase PS1 levels compensated for the cytotoxicity of full-length Ryk in these cells. These findings reveal that the Ryk-ICD pathway may impair FOXO protective activity in mutant polyglutamine neurons, suggesting that neurons are unable to efficiently maintain function and resist disease from the earliest phases of the pathogenic process in HD., Competing Interests: The authors have declared that no competing interests exist. Dr. Robert Ferrante is listed as an author of our paper, but at the time of acceptance was not reachable or able to confirm details of his author contributions to the manuscript. The corresponding author, Christian Neri, has therefore supplied the information regarding his contribution to the manuscript and his competing interests and it is correct to the best of Christian Neri's knowledge.
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- 2014
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10. Inhibition of mitochondrial protein import by mutant huntingtin.
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Yano H, Baranov SV, Baranova OV, Kim J, Pan Y, Yablonska S, Carlisle DL, Ferrante RJ, Kim AH, and Friedlander RM
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- Aged, Animals, Cells, Cultured, Female, HEK293 Cells, Humans, Huntingtin Protein, Huntington Disease pathology, Huntington Disease therapy, Male, Mice, Mice, Inbred CBA, Mice, Transgenic, Middle Aged, Mitochondria genetics, Mitochondria metabolism, Mitochondria pathology, Mitochondrial Proteins metabolism, Mutation, Nerve Tissue Proteins physiology, Protein Transport genetics, Huntington Disease genetics, Mitochondrial Proteins antagonists & inhibitors, Mitochondrial Proteins genetics, Nerve Tissue Proteins genetics
- Abstract
Mitochondrial dysfunction is associated with neuronal loss in Huntington's disease (HD), a neurodegenerative disease caused by an abnormal polyglutamine expansion in huntingtin (Htt). However, the mechanisms linking mutant Htt and mitochondrial dysfunction in HD remain unknown. We identify an interaction between mutant Htt and the TIM23 mitochondrial protein import complex. Remarkably, recombinant mutant Htt directly inhibited mitochondrial protein import in vitro. Furthermore, mitochondria from brain synaptosomes of presymptomatic HD model mice and from mutant Htt-expressing primary neurons exhibited a protein import defect, suggesting that deficient protein import is an early event in HD. The mutant Htt-induced mitochondrial import defect and subsequent neuronal death were attenuated by overexpression of TIM23 complex subunits, demonstrating that deficient mitochondrial protein import causes mutant Htt-induced neuronal death. Collectively, these findings provide evidence for a direct link between mutant Htt, mitochondrial dysfunction and neuronal pathology, with implications for mitochondrial protein import-based therapies in HD.
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- 2014
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11. Melatonin inhibits the caspase-1/cytochrome c/caspase-3 cell death pathway, inhibits MT1 receptor loss and delays disease progression in a mouse model of amyotrophic lateral sclerosis.
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Zhang Y, Cook A, Kim J, Baranov SV, Jiang J, Smith K, Cormier K, Bennett E, Browser RP, Day AL, Carlisle DL, Ferrante RJ, Wang X, and Friedlander RM
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- Amyotrophic Lateral Sclerosis genetics, Analysis of Variance, Animals, Caspase 3 metabolism, Cytochromes c metabolism, Disease Models, Animal, Disease Progression, Enzyme-Linked Immunosorbent Assay, Mice, Mice, Transgenic, Receptor, Melatonin, MT1 metabolism, Superoxide Dismutase genetics, Amyotrophic Lateral Sclerosis drug therapy, Antioxidants therapeutic use, Cell Death drug effects, Cell Death ethics, Melatonin therapeutic use, Signal Transduction drug effects
- Abstract
Caspase-mediated cell death contributes to the pathogenesis of motor neuron degeneration in the mutant SOD1(G93A) transgenic mouse model of amyotrophic lateral sclerosis (ALS), along with other factors such as inflammation and oxidative damage. By screening a drug library, we found that melatonin, a pineal hormone, inhibited cytochrome c release in purified mitochondria and prevented cell death in cultured neurons. In this study, we evaluated whether melatonin would slow disease progression in SOD1(G93A) mice. We demonstrate that melatonin significantly delayed disease onset, neurological deterioration and mortality in ALS mice. ALS-associated ventral horn atrophy and motor neuron death were also inhibited by melatonin treatment. Melatonin inhibited Rip2/caspase-1 pathway activation, blocked the release of mitochondrial cytochrome c, and reduced the overexpression and activation of caspase-3. Moreover, for the first time, we determined that disease progression was associated with the loss of both melatonin and the melatonin receptor 1A (MT1) in the spinal cord of ALS mice. These results demonstrate that melatonin is neuroprotective in transgenic ALS mice, and this protective effect is mediated through its effects on the caspase-mediated cell death pathway. Furthermore, our data suggest that melatonin and MT1 receptor loss may play a role in the pathological phenotype observed in ALS. The above observations indicate that melatonin and modulation of Rip2/caspase-1/cytochrome c or MT1 pathways may be promising therapeutic approaches for ALS., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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12. MAP kinase phosphatase 1 (MKP-1/DUSP1) is neuroprotective in Huntington's disease via additive effects of JNK and p38 inhibition.
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Taylor DM, Moser R, Régulier E, Breuillaud L, Dixon M, Beesen AA, Elliston L, Silva Santos Mde F, Kim J, Jones L, Goldstein DR, Ferrante RJ, and Luthi-Carter R
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- Animals, Cells, Cultured, Female, MAP Kinase Kinase 4 metabolism, Mice, Rats, Rats, Wistar, p38 Mitogen-Activated Protein Kinases metabolism, Dual Specificity Phosphatase 1 biosynthesis, Huntington Disease enzymology, Huntington Disease prevention & control, MAP Kinase Kinase 4 antagonists & inhibitors, Neuroprotective Agents metabolism, p38 Mitogen-Activated Protein Kinases antagonists & inhibitors
- Abstract
We previously demonstrated that sodium butyrate is neuroprotective in Huntington's disease (HD) mice and that this therapeutic effect is associated with increased expression of mitogen-activated protein kinase/dual-specificity phosphatase 1 (MKP-1/DUSP1). Here we show that enhancing MKP-1 expression is sufficient to achieve neuroprotection in lentiviral models of HD. Wild-type MKP-1 overexpression inhibited apoptosis in primary striatal neurons exposed to an N-terminal fragment of polyglutamine-expanded huntingtin (Htt171-82Q), blocking caspase-3 activation and significantly reducing neuronal cell death. This neuroprotective effect of MKP-1 was demonstrated to be dependent on its enzymatic activity, being ablated by mutation of its phosphatase domain and being attributed to inhibition of specific MAP kinases (MAPKs). Overexpression of MKP-1 prevented the polyglutamine-expanded huntingtin-induced activation of c-Jun N-terminal kinases (JNKs) and p38 MAPKs, whereas extracellular signal-regulated kinase (ERK) 1/2 activation was not altered by either polyglutamine-expanded Htt or MKP-1. Moreover, mutants of MKP-1 that selectively prevented p38 or JNK binding confirmed the important dual contributions of p38 and JNK regulation to MKP-1-mediated neuroprotection. These results demonstrate additive effects of p38 and JNK MAPK inhibition by MKP-1 without consequence to ERK activation in this striatal neuron-based paradigm. MKP-1 also provided neuroprotection in vivo in a lentiviral model of HD neuropathology in rat striatum. Together, these data extend previous evidence that JNK- and p38-mediated pathways contribute to HD pathogenesis and, importantly, show that therapies simultaneously inhibiting both JNK and p38 signaling pathways may lead to improved neuroprotective outcomes.
- Published
- 2013
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13. The sirtuin 2 inhibitor AK-7 is neuroprotective in Huntington's disease mouse models.
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Chopra V, Quinti L, Kim J, Vollor L, Narayanan KL, Edgerly C, Cipicchio PM, Lauver MA, Choi SH, Silverman RB, Ferrante RJ, Hersch S, and Kazantsev AG
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- Animals, Disease Models, Animal, Drug Evaluation, Preclinical, Female, Huntington Disease enzymology, Huntington Disease genetics, Male, Mice, Mice, Mutant Strains, Sirtuin 2 genetics, Sirtuin 2 metabolism, Histone Deacetylase Inhibitors pharmacology, Huntington Disease drug therapy, Neuroprotective Agents pharmacology, Sirtuin 2 antagonists & inhibitors
- Abstract
Inhibition of sirtuin 2 (SIRT2) deacetylase mediates protective effects in cell and invertebrate models of Parkinson's disease and Huntington's disease (HD). Here we report the in vivo efficacy of a brain-permeable SIRT2 inhibitor in two genetic mouse models of HD. Compound treatment resulted in improved motor function, extended survival, and reduced brain atrophy and is associated with marked reduction of aggregated mutant huntingtin, a hallmark of HD pathology. Our results provide preclinical validation of SIRT2 inhibition as a potential therapeutic target for HD and support the further development of SIRT2 inhibitors for testing in humans., (Copyright © 2012 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2012
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14. A call for transparent reporting to optimize the predictive value of preclinical research.
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Landis SC, Amara SG, Asadullah K, Austin CP, Blumenstein R, Bradley EW, Crystal RG, Darnell RB, Ferrante RJ, Fillit H, Finkelstein R, Fisher M, Gendelman HE, Golub RM, Goudreau JL, Gross RA, Gubitz AK, Hesterlee SE, Howells DW, Huguenard J, Kelner K, Koroshetz W, Krainc D, Lazic SE, Levine MS, Macleod MR, McCall JM, Moxley RT 3rd, Narasimhan K, Noble LJ, Perrin S, Porter JD, Steward O, Unger E, Utz U, and Silberberg SD
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- Animals, Publishing trends, Random Allocation, Sample Size, Statistics as Topic, Publishing standards, Research Design standards
- Abstract
The US National Institute of Neurological Disorders and Stroke convened major stakeholders in June 2012 to discuss how to improve the methodological reporting of animal studies in grant applications and publications. The main workshop recommendation is that at a minimum studies should report on sample-size estimation, whether and how animals were randomized, whether investigators were blind to the treatment, and the handling of data. We recognize that achieving a meaningful improvement in the quality of reporting will require a concerted effort by investigators, reviewers, funding agencies and journal editors. Requiring better reporting of animal studies will raise awareness of the importance of rigorous study design to accelerate scientific progress.
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- 2012
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15. A high-throughput screen to identify inhibitors of SOD1 transcription.
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Wright PD, Wightman N, Huang M, Weiss A, Sapp PC, Cuny GD, Ivinson AJ, Glicksman MA, Ferrante RJ, Matson W, Matson S, and Brown RH Jr
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- Animals, Blotting, Western, HeLa Cells, Humans, Mice, Mice, Transgenic, PC12 Cells, Polymerase Chain Reaction, Promoter Regions, Genetic, Rats, Structure-Activity Relationship, Superoxide Dismutase-1, Superoxide Dismutase genetics, Transcription, Genetic drug effects
- Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal degenerative motor neuron disease. Approximately 20 percent of familial ALS cases are caused by mutations in the Cu/Zn superoxide dismutase (SOD1) gene. Rodents expressing mutant SOD1 transgenes develop progressive, fatal motor neuron disease and disease onset and progression is dependent on the level of SOD1. We investigated the possibility that a reduction in SOD1 protein may be of therapeutic benefit in ALS and screened 30,000 compounds for inhibition of SOD1 transcription. The most effective inhibitor identified was N-{4-[4-(4-methylbenzoyl)-1-piperazinyl]phenyl}-2-thiophenecarboxamide (Compound ID 7687685), which in PC12 cells showed an EC50 of 10.6 microM for inhibition of SOD1 expression and an LD50 more than 30 microM. This compound was subsequently shown to reduce endogenous SOD1 levels in HeLa cells and to exhibit a modest reduction of SOD1 protein levels in mouse spinal cord tissue. These data suggest that the efficacy of compound 7687685 as an inhibitor of SOD1 gene expression is not likely to be clinically useful, although the strategy reported could be applied broadly to screening for small molecule inhibitors of gene expression.
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- 2012
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16. Chiral cyclohexane 1,3-diones as inhibitors of mutant SOD1-dependent protein aggregation for the treatment of ALS.
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Zhang Y, Benmohamed R, Zhang W, Kim J, Edgerly CK, Zhu Y, Morimoto RI, Ferrante RJ, Kirsch DR, and Silverman RB
- Abstract
Cyclohexane 1,3-diones were identified as a class of molecules exhibiting a protective effect against mutant SOD1 induced toxicity in PC-12 cells, but an optimized analogue had little or no effect on life extension in the G93A SOD1 mouse model for amyotrophic lateral sclerosis (ALS). Additional testing showed that these compounds were inactive in neurons and further analogue synthesis was carried out to identify compounds with neuronal activity. Starting from two racemic derivatives that were active in cortical neurons, two potent analogues (1b and 2b) were resolved, which were protective against mutant SOD1 induced toxicity in PC-12 cells. Both compounds were found to be active in cortical neurons and presented good ADME profiles in vitro. On the basis of these results, an ALS mouse trial with 1b was carried out, which showed slightly greater life extension than the FDA-approved ALS drug riluzole, thereby validating cyclohexane 1,3-diones as a novel therapeutic class for the treatment of ALS.
- Published
- 2012
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17. Cyclohexane 1,3-diones and their inhibition of mutant SOD1-dependent protein aggregation and toxicity in PC12 cells.
- Author
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Zhang W, Benmohamed R, Arvanites AC, Morimoto RI, Ferrante RJ, Kirsch DR, and Silverman RB
- Subjects
- Amino Acid Substitution, Amyotrophic Lateral Sclerosis drug therapy, Animals, Blood-Brain Barrier metabolism, Cyclohexanones therapeutic use, Cyclohexanones toxicity, Cyclopropanes therapeutic use, Cyclopropanes toxicity, Disease Models, Animal, Humans, Mice, Mice, Transgenic, Mutation, Neurons drug effects, PC12 Cells, Phenyl Ethers therapeutic use, Phenyl Ethers toxicity, Rats, Superoxide Dismutase genetics, Superoxide Dismutase metabolism, Superoxide Dismutase-1, Cyclohexanones chemistry, Cyclohexanones pharmacology, Cyclopropanes chemistry, Phenyl Ethers chemistry, Superoxide Dismutase antagonists & inhibitors
- Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. Currently, there is only one FDA-approved treatment for ALS (riluzole), and that drug only extends life, on average, by 2-3 months. Mutations in Cu/Zn superoxide dismutase (SOD1) are found in familial forms of the disease and have played an important role in the study of ALS pathophysiology. On the basis of their activity in a PC12-G93A-YFP high-throughput screening assay, several bioactive compounds have been identified and classified as cyclohexane-1,3-dione (CHD) derivatives. A concise and efficient synthetic route has been developed to provide diverse CHD analogs. The structural modification of the CHD scaffold led to the discovery of a more potent analog (26) with an EC(50) of 700 nM having good pharmacokinetic properties, such as high solubility, low human and mouse metabolic potential, and relatively good plasma stability. It was also found to efficiently penetrate the blood-brain barrier. However, compound 26 did not exhibit any significant life span extension in the ALS mouse model. It was found that, although 26 was active in PC12 cells, it had poor activity in other cell types, including primary cortical neurons, indicating that it can penetrate into the brain, but is not active in neuronal cells, potentially due to poor selective cell penetration. Further structural modification of the CHD scaffold was aimed at improving global cell activity as well as maintaining potency. Two new analogs (71 and 73) were synthesized, which had significantly enhanced cortical neuronal cell permeability, as well as similar potency to that of 26 in the PC12-G93A assay. These CHD analogs are being investigated further as novel therapeutic candidates for ALS., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2012
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18. ADME-guided design and synthesis of aryloxanyl pyrazolone derivatives to block mutant superoxide dismutase 1 (SOD1) cytotoxicity and protein aggregation: potential application for the treatment of amyotrophic lateral sclerosis.
- Author
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Chen T, Benmohamed R, Kim J, Smith K, Amante D, Morimoto RI, Kirsch DR, Ferrante RJ, and Silverman RB
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- Animals, Blood-Brain Barrier metabolism, Caco-2 Cells, Cell Membrane Permeability, Cytochrome P-450 Enzyme Inhibitors, Drug Design, ERG1 Potassium Channel, Ether-A-Go-Go Potassium Channels antagonists & inhibitors, Ethers chemical synthesis, Ethers pharmacokinetics, Ethers pharmacology, HEK293 Cells, Humans, In Vitro Techniques, Mice, Microsomes, Liver metabolism, Mutation, Neurons cytology, Neurons drug effects, Pyrazoles pharmacokinetics, Pyrazoles pharmacology, Pyrazolones pharmacokinetics, Pyrazolones pharmacology, Rats, Rats, Sprague-Dawley, Solubility, Structure-Activity Relationship, Sulfones chemical synthesis, Sulfones pharmacokinetics, Sulfones pharmacology, Superoxide Dismutase genetics, Superoxide Dismutase-1, Amyotrophic Lateral Sclerosis drug therapy, Pyrazoles chemical synthesis, Pyrazolones chemical synthesis, Superoxide Dismutase antagonists & inhibitors
- Abstract
Amyotrophic lateral sclerosis (ALS) is an orphan neurodegenerative disease currently without a cure. The arylsulfanyl pyrazolone (ASP) scaffold was one of the active scaffolds identified in a cell-based high throughput screening assay targeting mutant Cu/Zn superoxide dismutase 1 (SOD1) induced toxicity and aggregation as a marker for ALS. The initial ASP hit compounds were potent and had favorable ADME properties but had poor microsomal and plasma stability. Here, we identify the microsomal metabolite and describe synthesized analogues of these ASP compounds to address the rapid metabolism. Both in vitro potency and pharmacological properties of the ASP scaffold have been dramatically improved via chemical modification to the corresponding sulfone and ether derivatives. One of the ether analogues (13), with superior potency and in vitro pharmacokinetic properties, was tested in vivo for its pharmacokinetic profile, brain penetration, and efficacy in an ALS mouse model. The analogue showed sustained blood and brain levels in vivo and significant activity in the mouse model of ALS, thus validating the new aryloxanyl pyrazolone scaffold as an important novel therapeutic lead for the treatment of this neurodegenerative disorder.
- Published
- 2012
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19. Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway and is altered in Huntington disease.
- Author
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Keryer G, Pineda JR, Liot G, Kim J, Dietrich P, Benstaali C, Smith K, Cordelières FP, Spassky N, Ferrante RJ, Dragatsis I, and Saudou F
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- Animals, Brain metabolism, Brain pathology, Centrosome metabolism, Cilia genetics, Cilia metabolism, Cilia pathology, Disease Models, Animal, Humans, Huntingtin Protein, Huntington Disease pathology, Mice, Mice, Knockout, Microtubules metabolism, Peptides genetics, Signal Transduction, Trinucleotide Repeat Expansion, Autoantigens genetics, Autoantigens metabolism, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Huntington Disease genetics, Huntington Disease metabolism, Mutant Proteins genetics, Mutant Proteins metabolism, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Nuclear Proteins genetics, Nuclear Proteins metabolism
- Abstract
Huntington disease (HD) is a devastating autosomal-dominant neurodegenerative disorder. It is caused by expansion of a CAG repeat in the first exon of the huntingtin (HTT) gene that encodes a mutant HTT protein with a polyglutamine (polyQ) expansion at the amino terminus. Here, we demonstrate that WT HTT regulates ciliogenesis by interacting through huntingtin-associated protein 1 (HAP1) with pericentriolar material 1 protein (PCM1). Loss of Htt in mouse cells impaired the retrograde trafficking of PCM1 and thereby reduced primary cilia formation. In mice, deletion of Htt in ependymal cells led to PCM1 mislocalization, alteration of the cilia layer, and hydrocephalus. Pathogenic polyQ expansion led to centrosomal accumulation of PCM1 and abnormally long primary cilia in mouse striatal cells. PCM1 accumulation in ependymal cells was associated with longer cilia and disorganized cilia layers in a mouse model of HD and in HD patients. Longer cilia resulted in alteration of the cerebrospinal fluid flow. Thus, our data indicate that WT HTT is essential for protein trafficking to the centrosome and normal ciliogenesis. In HD, hypermorphic ciliogenesis may affect signaling and neuroblast migration so as to dysregulate brain homeostasis and exacerbate disease progression.
- Published
- 2011
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20. The melatonin MT1 receptor axis modulates mutant Huntingtin-mediated toxicity.
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Wang X, Sirianni A, Pei Z, Cormier K, Smith K, Jiang J, Zhou S, Wang H, Zhao R, Yano H, Kim JE, Li W, Kristal BS, Ferrante RJ, and Friedlander RM
- Subjects
- Analysis of Variance, Animals, Brain cytology, Brain drug effects, Brain metabolism, Caspase 3 analysis, Caspase 3 metabolism, Caspase 9 analysis, Caspase 9 metabolism, Cell Death drug effects, Cell Death genetics, Cells, Cultured, Disease Models, Animal, Embryo, Mammalian, Female, Gene Expression Regulation drug effects, Gene Expression Regulation genetics, Green Fluorescent Proteins genetics, Humans, Huntingtin Protein, Huntington Disease drug therapy, Huntington Disease pathology, Hydrogen Peroxide toxicity, Male, Melatonin therapeutic use, Mice, Mice, Mutant Strains, Middle Aged, Mitochondria drug effects, Mitochondria metabolism, Nerve Tissue Proteins metabolism, Neurons ultrastructure, Nuclear Proteins metabolism, Postmortem Changes, RNA, Messenger metabolism, RNA, Small Interfering pharmacology, Rats, Receptor, Melatonin, MT1 genetics, Receptor, Melatonin, MT2 genetics, Receptor, Melatonin, MT2 metabolism, Statistics, Nonparametric, Time Factors, Transfection methods, Huntington Disease metabolism, Melatonin pharmacology, Mutation genetics, Nerve Tissue Proteins genetics, Neurons drug effects, Neuroprotective Agents pharmacology, Nuclear Proteins genetics, Receptor, Melatonin, MT1 metabolism
- Abstract
Melatonin mediates neuroprotection in several experimental models of neurodegeneration. It is not yet known, however, whether melatonin provides neuroprotection in genetic models of Huntington's disease (HD). We report that melatonin delays disease onset and mortality in a transgenic mouse model of HD. Moreover, mutant huntingtin (htt)-mediated toxicity in cells, mice, and humans is associated with loss of the type 1 melatonin receptor (MT1). We observe high levels of MT1 receptor in mitochondria from the brains of wild-type mice but much less in brains from HD mice. Moreover, we demonstrate that melatonin inhibits mutant htt-induced caspase activation and preserves MT1 receptor expression. This observation is critical, because melatonin-mediated protection is dependent on the presence and activation of the MT1 receptor. In summary, we delineate a pathologic process whereby mutant htt-induced loss of the mitochondrial MT1 receptor enhances neuronal vulnerability and potentially accelerates the neurodegenerative process.
- Published
- 2011
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21. Transcriptional modulator H2A histone family, member Y (H2AFY) marks Huntington disease activity in man and mouse.
- Author
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Hu Y, Chopra V, Chopra R, Locascio JJ, Liao Z, Ding H, Zheng B, Matson WR, Ferrante RJ, Rosas HD, Hersch SM, and Scherzer CR
- Subjects
- Adult, Aged, Animals, Case-Control Studies, Cross-Sectional Studies, Disease Models, Animal, Double-Blind Method, Female, Frontal Lobe metabolism, Gene Expression, Histone Deacetylase Inhibitors pharmacology, Histones blood, Humans, Huntington Disease blood, Longitudinal Studies, Male, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Transgenic, Middle Aged, Nerve Degeneration drug therapy, RNA, Messenger genetics, RNA, Messenger metabolism, Histones genetics, Histones metabolism, Huntington Disease genetics, Huntington Disease metabolism
- Abstract
Huntington disease (HD) is a progressive neurodegenerative disease that affects 30,000 individuals in North America. Treatments that slow its relentless course are not yet available, and biomarkers that can reliably measure disease activity and therapeutic response are urgently needed to facilitate their development. Here, we interrogated 119 human blood samples for transcripts associated with HD. We found that the dynamic regulator of chromatin plasticity H2A histone family, member Y (H2AFY) is specifically overexpressed in the blood and frontal cortex of patients with HD compared with controls. This association precedes the onset of clinical symptoms, was confirmed in two mouse models, and was independently replicated in cross-sectional and longitudinal clinical studies comprising 142 participants. A histone deacetylase inhibitor that suppresses neurodegeneration in animal models reduces H2AFY levels in a randomized phase II clinical trial. This study identifies the chromatin regulator H2AFY as a potential biomarker associated with disease activity and pharmacodynamic response that may become useful for enabling disease-modifying therapeutics for HD.
- Published
- 2011
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22. Pyrimidine-2,4,6-trione derivatives and their inhibition of mutant SOD1-dependent protein aggregation. Toward a treatment for amyotrophic lateral sclerosis.
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Xia G, Benmohamed R, Kim J, Arvanites AC, Morimoto RI, Ferrante RJ, Kirsch DR, and Silverman RB
- Subjects
- Animals, Humans, Models, Molecular, Mutant Proteins genetics, PC12 Cells, Protein Structure, Quaternary, Pyrimidines chemical synthesis, Pyrimidines therapeutic use, Rats, Superoxide Dismutase genetics, Superoxide Dismutase-1, Amyotrophic Lateral Sclerosis drug therapy, Mutant Proteins chemistry, Mutation, Protein Multimerization drug effects, Pyrimidines chemistry, Pyrimidines pharmacology, Superoxide Dismutase chemistry
- Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons, leading to muscle weakness, paralysis, and death, most often from respiratory failure. The only FDA-approved drug for the treatment of ALS, riluzole, only extends the median survival in patients by 2-3 months. There is an urgent need for novel therapeutic strategies for this devastating disease. Using a high-throughput screening assay targeting an ALS cultured cell model (PC12-G93A-YFP cell line), we previously identified three chemotypes that were neuroprotective. We present a further detailed analysis of one promising scaffold from that group, pyrimidine-2,4,6-triones (PYTs), characterizing a number of PYT analogues using SAR and ADME. The PYT compounds show good potency, superior ADME data, low toxicity, brain penetration, and excellent oral bioavailability. Compounds from this series show 100% efficacy in the protection assay with a good correlation in activity between the protection and protein aggregation assays. The modifications of the PYT scaffold presented here suggest that this chemical structure may be a novel drug candidate scaffold for use in clinical trials in ALS.
- Published
- 2011
- Full Text
- View/download PDF
23. Identification of compounds protective against G93A-SOD1 toxicity for the treatment of amyotrophic lateral sclerosis.
- Author
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Benmohamed R, Arvanites AC, Kim J, Ferrante RJ, Silverman RB, Morimoto RI, and Kirsch DR
- Subjects
- Amyotrophic Lateral Sclerosis pathology, Amyotrophic Lateral Sclerosis physiopathology, Animals, Benzoquinones pharmacology, Cell Death drug effects, Cytoprotection, Drug Evaluation, Preclinical, High-Throughput Screening Assays, Humans, Lactams, Macrocyclic pharmacology, Leupeptins pharmacology, Macrolides pharmacology, Mutant Proteins metabolism, PC12 Cells, Rats, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Small Molecule Libraries, Superoxide Dismutase genetics, Amyotrophic Lateral Sclerosis drug therapy, Amyotrophic Lateral Sclerosis genetics, Drug Design, Superoxide Dismutase metabolism
- Abstract
The underlying cause of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disorder, remains unknown. However, there is strong evidence that one pathophysiological mechanism, toxic protein misfolding and/or aggregation, may trigger motor neuron dysfunction and loss. Since the clinical and pathological features of sporadic and familial ALS are indistinguishable, all forms of the disease may be better understood and ultimately treated by studying pathogenesis and therapy in models expressing mutant forms of SOD1. We developed a cellular model in which cell death depended on the expression of G93A-SOD1, a mutant form of superoxide dismutase found in familial ALS patients that produces toxic protein aggregates. This cellular model was optimized for high throughput screening to identify protective compounds from a >50,000 member chemical library. Three novel chemical scaffolds were selected for further study following screen implementation, counter-screening and secondary testing, including studies with purchased analogs. All three scaffolds blocked SOD1 aggregation in high content screening assays and data on the optimization and further characterization of these compounds will be reported separately. These data suggest that optimization of these chemicals scaffolds may produce therapeutic candidates for ALS patients.
- Published
- 2011
- Full Text
- View/download PDF
24. Arylsulfanyl pyrazolones block mutant SOD1-G93A aggregation. Potential application for the treatment of amyotrophic lateral sclerosis.
- Author
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Chen T, Benmohamed R, Arvanites AC, Ralay Ranaivo H, Morimoto RI, Ferrante RJ, Watterson DM, Kirsch DR, and Silverman RB
- Subjects
- Animals, Humans, Magnetic Resonance Spectroscopy, Mice, Spectrometry, Mass, Electrospray Ionization, Superoxide Dismutase genetics, Amyotrophic Lateral Sclerosis drug therapy, Enzyme Inhibitors pharmacology, Pyrazolones pharmacology, Superoxide Dismutase antagonists & inhibitors
- Abstract
Amyotrophic lateral sclerosis (ALS) is an orphan neurodegenerative disease currently without a cure. Mutations in copper/zinc superoxide dismutase 1 (SOD1) have been implicated in the pathophysiology of this disease. Using a high-throughput screening assay expressing mutant G93A SOD1, two bioactive chemical hit compounds (1 and 2), identified as arylsulfanyl pyrazolones, were identified. The structural optimization of this scaffold led to the generation of a more potent analogue (19) with an EC(50) of 170nM. To determine the suitability of this class of compounds for further optimization, 1 was subjected to a battery of pharmacokinetic assays; most of the properties of 1 were good for a screening hit, except it had a relatively rapid clearance and short microsomal half-life stability. Compound 2 was found to be blood-brain barrier penetrating with a brain/plasma ratio=0.19. The optimization of this class of compounds could produce novel therapeutic candidates for ALS patients., (Copyright © 2010. Published by Elsevier Ltd.)
- Published
- 2011
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- View/download PDF
25. Experimental models of HD and reflection on therapeutic strategies.
- Author
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Kim J, Bordiuk OL, and Ferrante RJ
- Subjects
- Animals, Disease Progression, Humans, Huntingtin Protein, Mice, Mice, Transgenic, Trinucleotide Repeat Expansion genetics, Disease Models, Animal, Huntington Disease genetics, Huntington Disease therapy, Nerve Tissue Proteins genetics, Nuclear Proteins genetics
- Abstract
Huntington's disease (HD) is an autosomal dominant, progressive, and fatal neurodegenerative disorder caused by an expanded polyglutamine cytosine-adenine-guanine repeat in the gene coding for the protein huntingtin. Despite great progress over the past two decades since the identification of the gene mutation, a direct causative pathway from the HD gene mutation to neuronal dysfunction and death has not yet been established. One important advance in understanding the pathogenic mechanisms of this disease has been the development of experimental mouse models that replicate many of the clinical, neuropathological, and molecular events in HD patients. These murine models have played a critical role in providing accurate and experimentally accessible systems to study multiple features of disease pathogenesis and to test potential therapeutic strategies. A better understanding of the pathophysiological mechanisms of disease and how they interrelate has become important in identifying a treatment for HD and in the design of human clinical trials. In this chapter, we review the current state of HD mouse models and their successes in elucidating disease pathogenesis and in developing pharmacotherapies. There is no clinically proven treatment for HD that can halt or ameliorate the inexorable disease progression. As such, a guide to assessing studies in mouse models and salient issues related to translation from mice to humans are included., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
26. Uridine ameliorates the pathological phenotype in transgenic G93A-ALS mice.
- Author
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Amante DJ, Kim J, Carreiro ST, Cooper AC, Jones SW, Li T, Moody JP, Edgerly CK, Bordiuk OL, Cormier K, Smith K, Ferrante RJ, and Rusche J
- Subjects
- 8-Hydroxy-2'-Deoxyguanosine, Amyotrophic Lateral Sclerosis genetics, Animals, Anterior Horn Cells drug effects, Anterior Horn Cells metabolism, Anterior Horn Cells pathology, Behavior, Animal drug effects, Behavior, Animal physiology, Body Weight drug effects, Deoxyguanosine analogs & derivatives, Deoxyguanosine urine, Disease Models, Animal, Dose-Response Relationship, Drug, Energy Metabolism physiology, Humans, Kaplan-Meier Estimate, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neuroprotective Agents pharmacology, Random Allocation, Rats, Rats, Sprague-Dawley, Spinal Cord cytology, Spinal Cord drug effects, Spinal Cord pathology, Superoxide Dismutase genetics, Survival Rate, Uridine pharmacology, Amyotrophic Lateral Sclerosis drug therapy, Amyotrophic Lateral Sclerosis pathology, Amyotrophic Lateral Sclerosis physiopathology, Neuroprotective Agents therapeutic use, Superoxide Dismutase metabolism, Uridine therapeutic use
- Abstract
There is strong evidence from studies in humans and animal models to suggest the involvement of energy metabolism defects in neurodegenerative diseases. Uridine, a pyrimidine nucleoside, has been suggested to be neuroprotective in neurological disorders by improving bioenergetic effects, increasing ATP levels and enhancing glycolytic energy production. We assessed whether uridine treatment extended survival and improved the behavioral and neuropathological phenotype observed in G93A-ALS mice. In vitro and in vivo pharmacokinetic analyses in mutant SOD models provided optimal dose and assurance that uridine entered the brain. A dose-ranging efficacy trial in G93A mice was performed using survival, body weight, open-field analysis, and neuropathology as outcome measures. Urinary levels of 8-hydroxy-2'-deoxyguanosine, identifying DNA oxidative damage, were measured and used as a pharmacodynamic biomarker. Uridine administration significantly extended survival in a dose-dependent manner in G93A mice, while improving the behavioral and neuropathological phenotype. Uridine increased survival by 17.4%, ameliorated body weight loss, enhanced motor performance, reduced gross lumbar and ventral horn atrophy, attenuated lumbar ventral horn neuronal cell death, and decreased reactive astrogliosis. Consistent with a therapeutic effect, uridine significantly reduced urinary 8-hydroxy-2'-deoxyguanosine in G93A mice. These data suggest that uridine may be a therapeutic candidate in ALS patients.
- Published
- 2010
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27. Mitochondrial loss, dysfunction and altered dynamics in Huntington's disease.
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Kim J, Moody JP, Edgerly CK, Bordiuk OL, Cormier K, Smith K, Beal MF, and Ferrante RJ
- Subjects
- Calbindins, Cytochromes c analysis, Cytochromes c immunology, DNA, Mitochondrial genetics, DNA, Mitochondrial metabolism, DNA-Binding Proteins metabolism, Dynamins, Electron Transport Complex IV analysis, Energy Metabolism, Fluorescent Antibody Technique, GTP Phosphohydrolases metabolism, Gene Expression, Gene Expression Profiling, Humans, Huntingtin Protein, Huntington Disease genetics, Membrane Potential, Mitochondrial, Membrane Transport Proteins metabolism, Microtubule-Associated Proteins metabolism, Mitochondria genetics, Mitochondrial Membrane Transport Proteins, Mitochondrial Proteins metabolism, Nerve Tissue Proteins genetics, Neurons chemistry, Neurons pathology, Nuclear Proteins genetics, Peroxisome Proliferator-Activated Receptors metabolism, Polymerase Chain Reaction, S100 Calcium Binding Protein G analysis, Superoxide Dismutase analysis, Superoxide Dismutase immunology, Transcription Factors metabolism, Huntington Disease metabolism, Huntington Disease pathology, Mitochondria metabolism, Mitochondria pathology, Neostriatum metabolism, Neostriatum ultrastructure
- Abstract
Although a direct causative pathway from the gene mutation to the selective neostriatal neurodegeneration remains unclear in Huntington's disease (HD), one putative pathological mechanism reported to play a prominent role in the pathogenesis of this neurological disorder is mitochondrial dysfunction. We examined mitochondria in preferentially vulnerable striatal calbindin-positive neurons in moderate-to-severe grade HD patients, using antisera against mitochondrial markers of COX2, SOD2 and cytochrome c. Combined calbindin and mitochondrial marker immunofluorescence showed a significant and progressive grade-dependent reduction in the number of mitochondria in spiny striatal neurons, with marked alteration in size. Consistent with mitochondrial loss, there was a reduction in COX2 protein levels using western analysis that corresponded with disease severity. In addition, both mitochondrial transcription factor A, a regulator of mtDNA, and peroxisome proliferator-activated receptor-co-activator gamma-1 alpha, a key transcriptional regulator of energy metabolism and mitochondrial biogenesis, were also significantly reduced with increasing disease severity. Abnormalities in mitochondrial dynamics were observed, showing a significant increase in the fission protein Drp1 and a reduction in the expression of the fusion protein mitofusin 1. Lastly, mitochondrial PCR array profiling in HD caudate nucleus specimens showed increased mRNA expression of proteins involved in mitochondrial localization, membrane translocation and polarization and transport that paralleled mitochondrial derangement. These findings reveal that there are both mitochondrial loss and altered mitochondrial morphogenesis with increased mitochondrial fission and reduced fusion in HD. These findings provide further evidence that mitochondrial dysfunction plays a critical role in the pathogenesis of HD.
- Published
- 2010
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28. In vivo expression of polyglutamine-expanded huntingtin by mouse striatal astrocytes impairs glutamate transport: a correlation with Huntington's disease subjects.
- Author
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Faideau M, Kim J, Cormier K, Gilmore R, Welch M, Auregan G, Dufour N, Guillermier M, Brouillet E, Hantraye P, Déglon N, Ferrante RJ, and Bonvento G
- Subjects
- Aged, Amino Acid Transport System X-AG metabolism, Animals, Astrocytes pathology, Biological Transport, Dopamine and cAMP-Regulated Phosphoprotein 32 metabolism, Down-Regulation, Fluorescent Antibody Technique, Glial Fibrillary Acidic Protein metabolism, Humans, Huntington Disease pathology, Lentivirus genetics, Mice, Middle Aged, Mutant Proteins metabolism, Neostriatum metabolism, Neurons metabolism, Neurons pathology, Phenotype, Receptors, N-Methyl-D-Aspartate metabolism, Time Factors, Astrocytes metabolism, Glutamic Acid metabolism, Huntington Disease metabolism, Neostriatum pathology, Peptides metabolism, Serotonin Plasma Membrane Transport Proteins metabolism, Trinucleotide Repeat Expansion genetics
- Abstract
Huntington's disease (HD) is a neurodegenerative disorder previously thought to be of primary neuronal origin, despite ubiquitous expression of mutant huntingtin (mHtt). We tested the hypothesis that mHtt expressed in astrocytes may contribute to the pathogenesis of HD. To better understand the contribution of astrocytes in HD in vivo, we developed a novel mouse model using lentiviral vectors that results in selective expression of mHtt into striatal astrocytes. Astrocytes expressing mHtt developed a progressive phenotype of reactive astrocytes that was characterized by a marked decreased expression of both glutamate transporters, GLAST and GLT-1, and of glutamate uptake. These effects were associated with neuronal dysfunction, as observed by a reduction in DARPP-32 and NR2B expression. Parallel studies in brain samples from HD subjects revealed early glial fibrillary acidic protein expression in striatal astrocytes from Grade 0 HD cases. Astrogliosis was associated with morphological changes that increased with severity of disease, from Grades 0 through 4 and was more prominent in the putamen. Combined immunofluorescence showed co-localization of mHtt in astrocytes in all striatal HD specimens, inclusive of Grade 0 HD. Consistent with the findings from experimental mice, there was a significant grade-dependent decrease in striatal GLT-1 expression from HD subjects. These findings suggest that the presence of mHtt in astrocytes alters glial glutamate transport capacity early in the disease process and may contribute to HD pathogenesis.
- Published
- 2010
- Full Text
- View/download PDF
29. Reduced creatine kinase as a central and peripheral biomarker in Huntington's disease.
- Author
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Kim J, Amante DJ, Moody JP, Edgerly CK, Bordiuk OL, Smith K, Matson SA, Matson WR, Scherzer CR, Rosas HD, Hersch SM, and Ferrante RJ
- Subjects
- Aged, Animals, Biomarkers analysis, Biomarkers blood, Biomarkers metabolism, Case-Control Studies, Down-Regulation, Female, Humans, Huntington Disease diagnosis, Huntington Disease pathology, Male, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Transgenic, Middle Aged, Postmortem Changes, Central Nervous System metabolism, Creatine Kinase, BB Form blood, Creatine Kinase, BB Form metabolism, Huntington Disease blood, Huntington Disease metabolism
- Abstract
A major goal of current clinical research in Huntington's disease (HD) has been to identify preclinical and manifest disease biomarkers, as these may improve both diagnosis and the power for therapeutic trials. Although the underlying biochemical alterations and the mechanisms of neuronal degeneration remain unknown, energy metabolism defects in HD have been chronicled for many years. We report that the brain isoenzyme of creatine kinase (CK-BB), an enzyme important in buffering energy stores, was significantly reduced in presymptomatic and manifest disease in brain and blood buffy coat specimens in HD mice and HD patients. Brain CK-BB levels were significantly reduced in R6/2 mice by approximately 18% to approximately 68% from 21 to 91 days of age, while blood CK-BB levels were decreased by approximately 14% to approximately 44% during the same disease duration. Similar findings in CK-BB levels were observed in the 140 CAG mice from 4 to 12 months of age, but not at the earliest time point, 2 months of age. Consistent with the HD mice, there was a grade-dependent loss of brain CK-BB that worsened with disease severity in HD patients from approximately 28% to approximately 63%, as compared to non-diseased control patients. In addition, CK-BB blood buffy coat levels were significantly reduced in both premanifest and symptomatic HD patients by approximately 23% and approximately 39%, respectively. The correlation of CK-BB as a disease biomarker in both CNS and peripheral tissues from HD mice and HD patients may provide a powerful means to assess disease progression and to predict the potential magnitude of therapeutic benefit in this disorder., (Published by Elsevier B.V.)
- Published
- 2010
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- View/download PDF
30. Activation of Ets-2 by oxidative stress induces Bcl-xL expression and accounts for glial survival in amyotrophic lateral sclerosis.
- Author
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Lee J, Kannagi M, Ferrante RJ, Kowall NW, and Ryu H
- Subjects
- Animals, Cells, Cultured, Disease Models, Animal, Female, Glial Fibrillary Acidic Protein metabolism, Humans, Male, Mice, Mice, Transgenic, Motor Neurons cytology, Motor Neurons metabolism, NF-kappa B genetics, NF-kappa B metabolism, Neuroglia cytology, Oxidative Stress, Promoter Regions, Genetic, Proto-Oncogene Protein c-ets-2 genetics, RNA Interference, Sp1 Transcription Factor genetics, Sp1 Transcription Factor metabolism, Superoxide Dismutase genetics, Superoxide Dismutase metabolism, bcl-X Protein genetics, Amyotrophic Lateral Sclerosis metabolism, Cell Survival physiology, Neuroglia physiology, Proto-Oncogene Protein c-ets-2 metabolism, bcl-X Protein metabolism
- Abstract
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by selective degeneration of motor neurons and glial activation. Cell-specific transcriptional regulation induced by oxidative stress may contribute to the survival and activation of astrocytes in the face of motor neuron death. In the present study, we demonstrate an age-dependent increase in Bcl-xL and Ets-2 immunoreactivity that correlates with an increase of glial fibrillary acidic protein (GFAP)-positive cells in the ventral horn of the spinal cord in both ALS transgenic mice [mutant SOD1 (G93A)] and affected humans. Chromatin immunoprecipitation (ChIP) analysis verified that Ets-2 preferentially occupies the Ets-2 binding element in the promoter of Bcl-xL in primary astrocytes under oxidative stress conditions as well as in G93A spinal cords. Ets-2 small-interfering RNA down-regulated the transcriptional activity of Bcl-xL. In primary glial cultures, Bcl-xL overexpression and mutant SOD1 (G93A) both conferred resistance to oxidative stress-induced cell death. Our findings suggest that Ets-2 transcription factor activation of Bcl-xL gene may protect glia from constitutive oxidative stress that is thought to be a key mechanism contributing to the pathogenesis of ALS. This survival pathway may contribute to the glial survival and activation seen in the spinal cord of ALS patients.
- Published
- 2009
- Full Text
- View/download PDF
31. Mouse models of Huntington's disease and methodological considerations for therapeutic trials.
- Author
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Ferrante RJ
- Subjects
- Animals, Biomarkers analysis, Drug Evaluation, Preclinical, Energy Metabolism, Humans, Huntingtin Protein, Huntington Disease genetics, Huntington Disease therapy, Mice, Mice, Transgenic, Nerve Tissue Proteins genetics, Neurotoxins metabolism, Nuclear Proteins genetics, Treatment Outcome, Disease Models, Animal, Huntington Disease etiology
- Abstract
Huntington's disease (HD) is an autosomal dominant, progressive, and fatal neurodegenerative disorder caused by an expanded polyglutamine cytosine-adenine-guanine repeat in the gene coding for the protein huntingtin. Despite great progress, a direct causative pathway from the HD gene mutation to neuronal dysfunction and death has not yet been established. One important advance in understanding the pathogenic mechanisms of this disease has been the development of multiple murine models that replicate many of the clinical, neuropathological, and molecular events in HD patients. These models have played an important role in providing accurate and experimentally accessible systems to study multiple aspects of disease pathogenesis and to test potential therapeutic treatment strategies. Understanding how disease processes interrelate has become important in identifying a pharmacotherapy in HD and in the design of clinical trials. A review of the current state of HD mouse models and their successes in elucidating disease pathogenesis are discussed. There is no clinically proven treatment for HD that can halt or ameliorate the inexorable disease progression. As such, a guide to assessing studies in mouse models and salient issues related to translation from mice to humans are included.
- Published
- 2009
- Full Text
- View/download PDF
32. Combination therapy with coenzyme Q10 and creatine produces additive neuroprotective effects in models of Parkinson's and Huntington's diseases.
- Author
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Yang L, Calingasan NY, Wille EJ, Cormier K, Smith K, Ferrante RJ, and Beal MF
- Subjects
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 8-Hydroxy-2'-Deoxyguanosine, Analysis of Variance, Animals, Chromatography, High Pressure Liquid methods, Deoxyguanosine analogs & derivatives, Deoxyguanosine metabolism, Disease Models, Animal, Dopamine metabolism, Drug Therapy, Combination, Glutathione metabolism, Glutathione Disulfide metabolism, Huntington Disease chemically induced, Lipid Peroxidation drug effects, Male, Malondialdehyde metabolism, Mice, Mice, Inbred C57BL, Nitro Compounds, Parkinson Disease etiology, Propionates, Rats, Rats, Inbred Lew, Tyrosine 3-Monooxygenase metabolism, Ubiquinone therapeutic use, alpha-Synuclein metabolism, Creatine therapeutic use, Huntington Disease drug therapy, Neuroprotective Agents therapeutic use, Parkinson Disease drug therapy, Ubiquinone analogs & derivatives
- Abstract
Coenzyme Q(10) (CoQ(10)) and creatine are promising agents for neuroprotection in neurodegenerative diseases via their effects on improving mitochondrial function and cellular bioenergetics and their properties as antioxidants. We examined whether a combination of CoQ(10) with creatine can exert additive neuroprotective effects in a MPTP mouse model of Parkinson's disease, a 3-NP rat model of Huntington's disease (HD) and the R6/2 transgenic mouse model of HD. The combination of the two agents produced additive neuroprotective effects against dopamine depletion in the striatum and loss of tyrosine hydroxylase neurons in the substantia nigra pars compacta (SNpc) following chronic subcutaneous administration of MPTP. The combination treatment resulted in significant reduction in lipid peroxidation and pathologic alpha-synuclein accumulation in the SNpc neurons of the MPTP-treated mice. We also observed additive neuroprotective effects in reducing striatal lesion volumes produced by chronic subcutaneous administration of 3-NP to rats. The combination treatment showed significant effects on blocking 3-NP-induced impairment of glutathione homeostasis and reducing lipid peroxidation and DNA oxidative damage in the striatum. Lastly, the combination of CoQ(10) and creatine produced additive neuroprotective effects on improving motor performance and extending survival in the transgenic R6/2 HD mice. These findings suggest that combination therapy using CoQ(10) and creatine may be useful in the treatment of neurodegenerative diseases such as Parkinson's disease and HD.
- Published
- 2009
- Full Text
- View/download PDF
33. SCAMP5 links endoplasmic reticulum stress to the accumulation of expanded polyglutamine protein aggregates via endocytosis inhibition.
- Author
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Noh JY, Lee H, Song S, Kim NS, Im W, Kim M, Seo H, Chung CW, Chang JW, Ferrante RJ, Yoo YJ, Ryu H, and Jung YK
- Subjects
- Animals, Brain embryology, Endocytosis, Humans, Huntingtin Protein, Mice, Mice, Transgenic, Mutation, Nerve Tissue Proteins genetics, Nuclear Proteins genetics, Rats, Serotonin Plasma Membrane Transport Proteins genetics, Carrier Proteins metabolism, Endoplasmic Reticulum metabolism, Membrane Proteins metabolism, Peptides metabolism, Up-Regulation
- Abstract
Accumulation of expanded polyglutamine proteins is considered to be a major pathogenic biomarker of Huntington disease. We isolated SCAMP5 as a novel regulator of cellular accumulation of expanded polyglutamine track protein using cell-based aggregation assays. Ectopic expression of SCAMP5 augments the formation of ubiquitin-positive and detergent-resistant aggregates of mutant huntingtin (mtHTT). Expression of SCAMP5 is markedly increased in the striatum of Huntington disease patients and is induced in cultured striatal neurons by endoplasmic reticulum (ER) stress or by mtHTT. The increase of SCAMP5 impairs endocytosis, which in turn enhances mtHTT aggregation. On the contrary, down-regulation of SCAMP5 alleviates ER stress-induced mtHTT aggregation and endocytosis inhibition. Moreover, stereotactic injection into the striatum and intraperitoneal injection of tunicamycin significantly increase mtHTT aggregation in the striatum of R6/2 mice and in the cortex of N171-82Q mice, respectively. Taken together, these results suggest that exposure to ER stress increases SCAMP5 in the striatum, which positively regulates mtHTT aggregation via the endocytosis pathway.
- Published
- 2009
- Full Text
- View/download PDF
34. Combined riluzole and sodium phenylbutyrate therapy in transgenic amyotrophic lateral sclerosis mice.
- Author
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Del Signore SJ, Amante DJ, Kim J, Stack EC, Goodrich S, Cormier K, Smith K, Cudkowicz ME, and Ferrante RJ
- Subjects
- Acetylation drug effects, Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis mortality, Animals, Anterior Horn Cells drug effects, Body Weight drug effects, Drug Synergism, Drug Therapy, Combination, Female, Histones metabolism, Humans, Male, Mice, Mice, Transgenic, Muscle Strength drug effects, NF-kappa B p50 Subunit metabolism, Phenotype, Superoxide Dismutase genetics, Superoxide Dismutase-1, Amyotrophic Lateral Sclerosis drug therapy, Neuroprotective Agents pharmacology, Phenylbutyrates pharmacology, Riluzole pharmacology
- Abstract
Recent evidence suggests that transcriptional dysregulation may play a role in the pathogenesis of amyotrophic lateral sclerosis (ALS). The histone deacetylase inhibitor, sodium phenylbutyrate (NaPB), is neuroprotective and corrects aberrant gene transcription in ALS mice and has recently been shown to be safe and tolerable in ALS patients while improving hypoacetylation. Since many patients are already on riluzole, it is important to ensure that any proposed therapy does not result in negative synergy with riluzole. The combined treatment of riluzole and NaPB significantly extended survival and improved both the clinical and neuropathological phenotypes in G93A transgenic ALS mice beyond either agent alone. Combination therapy increased survival by 21.5%, compared to the separate administration of riluzole (7.5%) and NaPB (12.8%), while improving both body weight loss and grip strength. The data show that the combined treatment was synergistic. In addition, riluzole/NaPB treatment ameliorated gross lumbar and ventral horn atrophy, attenuated lumbar ventral horn neuronal cell death, and decreased reactive astrogliosis. Riluzole/NaPB administration increased acetylation at H4 and increased NF-kappaB p50 translocation to the nucleus in G93A mice, consistent with a therapeutic effect. These data suggest that NaPB may not interfere with the pharmacologic action of riluzole in ALS patients.
- Published
- 2009
- Full Text
- View/download PDF
35. Phase 2 study of sodium phenylbutyrate in ALS.
- Author
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Cudkowicz ME, Andres PL, Macdonald SA, Bedlack RS, Choudry R, Brown RH Jr, Zhang H, Schoenfeld DA, Shefner J, Matson S, Matson WR, and Ferrante RJ
- Subjects
- Aged, Anticonvulsants administration & dosage, Anticonvulsants blood, Dose-Response Relationship, Drug, Drug Therapy, Combination, Enzyme Inhibitors adverse effects, Female, Histone Deacetylases metabolism, Humans, Male, Middle Aged, Motor Neurons drug effects, Motor Neurons enzymology, Phenylacetates administration & dosage, Phenylacetates blood, Phenylbutyrates adverse effects, Amyotrophic Lateral Sclerosis drug therapy, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors pharmacokinetics, Histone Deacetylase Inhibitors, Phenylbutyrates administration & dosage, Phenylbutyrates pharmacokinetics
- Abstract
The objective of the study was to establish the safety and pharmacodynamics of escalating dosages of sodium phenylbutyrate (NaPB) in participants with ALS. Transcription dysregulation may play a role in the pathogenesis of ALS. Sodium phenylbutyrate, a histone deacetylase inhibitor, improves transcription and post-transcriptional pathways, promoting cell survival in a mouse model of motor neuron disease. Forty research participants at eight sites enrolled in an open-label study. Study medication was increased from 9 to 21 g/day. The primary outcome measure was tolerability. Secondary outcome measures included adverse events, blood histone acetylation levels, and NaPB blood levels at each dosage. Twenty-six participants completed the 20-week treatment phase. NaPB was safe and tolerable. No study deaths or clinically relevant laboratory changes occurred with NaPB treatment. Histone acetylation was decreased by approximately 50% in blood buffy-coat specimens at screening and was significantly increased after NaPB administration. Blood levels of NaPB and the primary metabolite, phenylacetate, increased with dosage. While the majority of subjects tolerated higher dosages of NaPB, the lowest dose (9 g/day), was therapeutically efficient in improving histone acetylation levels.
- Published
- 2009
- Full Text
- View/download PDF
36. Evidence of oxidant damage in Huntington's disease: translational strategies using antioxidants.
- Author
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Stack EC, Matson WR, and Ferrante RJ
- Subjects
- Animals, Humans, Oxidative Stress, Huntington Disease metabolism, Oxidants metabolism
- Abstract
Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder characterized by progressive motor dysfunction, emotional disturbances, dementia, and weight loss. It is caused by an expanded trinucleotide CAG repeat in the gene coding for the protein, huntingtin. Although no one specific interaction of mutant huntingtin has been suggested to be the pathologic trigger, a large body of evidence suggests that, in both the human condition and in HD mice, oxidative stress may play a role in the pathogenesis of HD. Increased levels of oxidative damage products, including protein nitration, lipid peroxidation, DNA oxidation, and exacerbated lipofuscin accumulation, occur in HD. Strong evidence exists for early oxidative stress in HD, coupled with mitochondrial dysfunction, each exacerbating the other and leading to an energy deficit. If oxidative damage plays a role in HD, then therapeutic strategies that reduce reactive oxygen species may ameliorate the neurodegenerative process. Two such strategies, using coenzyme Q(10) and creatine, have been proposed. Although each agent has had limited efficacy in HD patients, the optimal therapeutic dose may have been underestimated. High-dose coenzyme Q(10) and creatine are safe and tolerable in HD patients and are currently under investigation. In addition, there are parallels in reducing markers of oxidative stress in both HD mice and HD patients after treatment. It is likely that high-dose coenzyme Q(10), creatine, or both agents, will represent a cornerstone defense in ameliorating the progression of HD.
- Published
- 2008
- Full Text
- View/download PDF
37. Inhibitors of cytochrome c release with therapeutic potential for Huntington's disease.
- Author
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Wang X, Zhu S, Pei Z, Drozda M, Stavrovskaya IG, Del Signore SJ, Cormier K, Shimony EM, Wang H, Ferrante RJ, Kristal BS, and Friedlander RM
- Subjects
- Animals, Brain metabolism, Brain physiopathology, Carbonic Anhydrase Inhibitors pharmacology, Carbonic Anhydrase Inhibitors therapeutic use, Caspases drug effects, Caspases metabolism, Cell Death drug effects, Cell Death physiology, Cell Line, Transformed, Cytochromes c metabolism, Disease Models, Animal, Drug Evaluation, Preclinical, Huntington Disease metabolism, Huntington Disease physiopathology, Longevity drug effects, Longevity physiology, Membrane Potential, Mitochondrial drug effects, Membrane Potential, Mitochondrial physiology, Methazolamide pharmacology, Methazolamide therapeutic use, Mice, Mice, Transgenic, Mitochondria metabolism, Neuroprotective Agents therapeutic use, Treatment Outcome, Brain drug effects, Cytochromes c antagonists & inhibitors, Huntington Disease drug therapy, Mitochondria drug effects, Neuroprotective Agents pharmacology
- Abstract
Release of mitochondrial cytochrome c resulting in downstream activation of cell death pathways has been suggested to play a role in neurologic diseases featuring cell death. However, the specific biologic importance of cytochrome c release has not been demonstrated in Huntington's disease (HD). To evaluate the role of cytochrome c release, we screened a drug library to identify new inhibitors of cytochrome c release from mitochondria. Drugs effective at the level of purified mitochondria were evaluated in a cellular model of HD. As proof of principle, one drug was chosen for in depth evaluation in vitro and a transgenic mouse model of HD. Our findings demonstrate the utility of mitochondrial screening to identify inhibitors of cell death and provide further support for the important functional role of cytochrome c release in HD. Given that many of these compounds have been approved by the Food and Drug Administration for clinical usage and cross the blood-brain barrier, these drugs may lead to trials in patients.
- Published
- 2008
- Full Text
- View/download PDF
38. Monoallele deletion of CBP leads to pericentromeric heterochromatin condensation through ESET expression and histone H3 (K9) methylation.
- Author
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Lee J, Hagerty S, Cormier KA, Kim J, Kung AL, Ferrante RJ, and Ryu H
- Subjects
- Animals, Gene Deletion, Histone-Lysine N-Methyltransferase, Methylation, Mice, Mice, Inbred C57BL, CREB-Binding Protein genetics, CREB-Binding Protein metabolism, Heterochromatin metabolism, Histones metabolism, Neurons metabolism, Protein Methyltransferases metabolism
- Abstract
Chromatin remodeling is tightly controlled under physiological conditions. Alterations in chromatin structure are involved in the pathogenesis of neuronal systems. We found that the monoallelic deletion of CREB binding protein (CBP) results in the induction of ERG-associated protein with SET domain (ESET) and increases trimethylation of histone H3 (K9) and condensation of pericentromeric heterochromatin structure in neurons. Nested deletion and mutational analysis of the ESET promoter further demonstrated that the Ets-2 transcription factor regulates transcriptional activity of the ESET gene. In CBP+/- mice, Ets-2 occupancy in the ESET promoter DNA was markedly elevated. Our results suggest that CBP is a transcriptional repressor of ESET gene expression by limiting Ets-2 transcriptional activity, while CBP siRNA enhances basal and Ets-2-dependent ESET transcriptional activity. Altered expression of the ESET gene and hypertrimethylation of H3 (K9) correlate with striatal neuron atrophy and dysfunction in CBP+/- mice. These results establish an alternative pathway that loss of CBP leads to the pericentric heterochromatin condensation through ESET expression and trimethylation of H3 (K9).
- Published
- 2008
- Full Text
- View/download PDF
39. Mitochondrial nuclear receptors and transcription factors: who's minding the cell?
- Author
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Lee J, Sharma S, Kim J, Ferrante RJ, and Ryu H
- Subjects
- Active Transport, Cell Nucleus genetics, Animals, Cell Nucleus genetics, Energy Metabolism genetics, Humans, Mitochondria genetics, Mitochondrial Diseases drug therapy, Mitochondrial Diseases genetics, Mitochondrial Diseases metabolism, Receptors, Cytoplasmic and Nuclear genetics, Signal Transduction genetics, Transcription Factors genetics, Cell Nucleus metabolism, Mitochondria metabolism, Receptors, Cytoplasmic and Nuclear metabolism, Transcription Factors metabolism
- Abstract
Mitochondria are power organelles generating biochemical energy, ATP, in the cell. Mitochondria play a variety of roles, including integrating extracellular signals and executing critical intracellular events, such as neuronal cell survival and death. Increasing evidence suggests that a cross-talk mechanism between mitochondria and the nucleus is closely related to neuronal function and activity. Nuclear receptors (estrogen receptors, thyroid (T3) hormone receptor, peroxisome proliferators-activated receptor gamma2) and transcription factors (cAMP response binding protein, p53) have been found to target mitochondria and exert prosurvival and prodeath pathways. In this context, the regulation of mitochondrial function via the translocation of nuclear receptors and transcription factors may underlie some of the mechanisms involved in neuronal survival and death. Understanding the function of nuclear receptors and transcription factors in the mitochondria may provide important pharmacological utility in the treatment of neurodegenerative conditions. Thus, the modulation of signaling pathways via mitochondria-targeting nuclear receptors and transcription factors is rapidly emerging as a novel therapeutic target.
- Published
- 2008
- Full Text
- View/download PDF
40. Therapeutic attenuation of mitochondrial dysfunction and oxidative stress in neurotoxin models of Parkinson's disease.
- Author
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Stack EC, Ferro JL, Kim J, Del Signore SJ, Goodrich S, Matson S, Hunt BB, Cormier K, Smith K, Matson WR, Ryu H, and Ferrante RJ
- Subjects
- Animals, Brain cytology, Brain metabolism, Drug Evaluation, Preclinical, Male, Parkinson Disease etiology, Parkinson Disease pathology, Parkinson Disease physiopathology, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Cystamine therapeutic use, Disease Models, Animal, Mitochondrial Diseases drug therapy, Neurotoxins, Oxidative Stress drug effects, Oxidopamine, Parkinson Disease drug therapy
- Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disorder for which there is no current therapy preventing cumulative neuronal loss. There is substantial evidence that mitochondrial dysfunction, oxidative stress, and associated caspase activity underlie the neurodegeneration observed. One potential drug therapy is the potent free radical scavenger and antioxidant cystamine, which has demonstrated significant clinical potential in models of neurodegenerative disorders and human neurological disease. This study examined the oral efficacy of cystamine in the MPTP and 6-hydroxydopamine neurotoxin models of PD. The neuroprotective effects of cystamine treatment significantly ameliorated nigral neuronal loss, preserved striatal dopaminergic projections, and improved striatal dopamine and metabolite levels, as compared to MPTP alone. Cystamine normalized striatal 8-hydroxy-2'-deoxyguanosine levels and ATP concentrations, consistent with reduced oxidative stress and improved mitochondrial function. Cystamine also protected against MPTP-induced mitochondrial loss, as identified by mitochondrial heat shock protein 70 and superoxide dismutase 2, with concomitant reductions in cytochrome c and caspase-3 activities. The neuroprotective value of cystamine was confirmed in the 6-hydroxydopamine model. Together these findings show cystamine's therapeutic benefit to reduce neuronal loss through attenuation of oxidative stress and mitochondrial dysfunction, providing the rationale for human clinical trials in PD patients.
- Published
- 2008
- Full Text
- View/download PDF
41. Huntington's disease: progress and potential in the field.
- Author
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Stack EC and Ferrante RJ
- Subjects
- Animals, Cell Death drug effects, Cell Death physiology, Clinical Trials as Topic, Drug Delivery Systems trends, Drugs, Investigational chemistry, Drugs, Investigational pharmacology, Humans, Huntington Disease metabolism, Huntington Disease pathology, Drugs, Investigational therapeutic use, Huntington Disease drug therapy
- Abstract
While the first description of Huntington's disease was reported over a century ago, no therapy exists that can halt or ameliorate the inexorable disease progression. Tremendous progress, however, has been made in significantly broadening the understanding of pathogenic mechanisms in this neurological disorder that may eventually lead to successful treatment strategies. Huntington's disease is caused by the expansion of a CAG repeat in the huntingtin gene, which results in the expression of a mutant form of the protein that is toxic to neurons. Several mechanisms have been identified in mediating this toxicity, such as protein aggregation, mitochondrial dysfunction, oxidative stress, transcriptional dysregulation, aberrant apoptosis, altered proteosomal function and excitotoxicity. With increasing understanding of each of these pathogenic mechanisms, therapeutic strategies have attempted to target specific aspects of each. There have been many encouraging reports of preclinical efficacy in transgenic Huntington's disease mice, from which a number have been extended to human clinical trials with some success. This review focuses on these studies and the compounds that hold promise for treating human Huntington's disease.
- Published
- 2007
- Full Text
- View/download PDF
42. Neuroprotective effects of synaptic modulation in Huntington's disease R6/2 mice.
- Author
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Stack EC, Dedeoglu A, Smith KM, Cormier K, Kubilus JK, Bogdanov M, Matson WR, Yang L, Jenkins BG, Luthi-Carter R, Kowall NW, Hersch SM, Beal MF, and Ferrante RJ
- Subjects
- Animals, Cerebral Cortex metabolism, Cerebral Cortex pathology, Female, Huntington Disease prevention & control, Mice, Mice, Inbred CBA, Mice, Transgenic, Neostriatum metabolism, Neostriatum pathology, Nerve Degeneration metabolism, Nerve Degeneration pathology, Nerve Degeneration prevention & control, Neural Pathways metabolism, Disease Models, Animal, Huntington Disease metabolism, Huntington Disease pathology, Synapses metabolism, Synapses pathology
- Abstract
Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder in which the neostriatum degenerates early and most severely, with involvement of other brain regions. There is significant evidence that excitotoxicity may play a role in striatal degeneration through altered afferent corticostriatal and nigrostriatal projections that may modulate synaptically released striatal glutamate. Glutamate is a central tenant in provoking excitotoxic cell death in striatal neurons already weakened by the collective molecular events occurring in HD. In addition, transcriptional suppression of trophic factors occurs in human and transgenic mouse models of HD, suggesting that a loss of trophic support might contribute to degeneration. Since anti-glutamate approaches have been effective in improving disease phenotype in HD mice, we examined whether deafferentation of the corticostriatal and nigrostriatal pathways may mitigate striatal stress and neurodegeneration. Both surgical and chemical lesions of the corticostriatal and nigrostriatal pathways, respectively, improved the behavioral, neuropathological, and biochemical phenotype in R6/2 transgenic mice and extended survival. Decortication ameliorated hindlimb clasping, striatal neuron atrophy, and huntingtin-positive aggregates, improved N-acetyl aspartate/creatine levels, reduced oxidative stress, and significantly lowered striatal glutamate levels. In addition, 6-hydroxydopamine lesioned mice showed extended survival along with a significant reduction in striatal glutamate. These results suggest that synaptic stress is likely to contribute to neurodegeneration in HD, whereas transsynaptic trophic influences may not be as salient. Thus, modulation of synaptic influences continues to have therapeutic potential in HD.
- Published
- 2007
- Full Text
- View/download PDF
43. Mutant huntingtin's effects on striatal gene expression in mice recapitulate changes observed in human Huntington's disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage.
- Author
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Kuhn A, Goldstein DR, Hodges A, Strand AD, Sengstag T, Kooperberg C, Becanovic K, Pouladi MA, Sathasivam K, Cha JH, Hannan AJ, Hayden MR, Leavitt BR, Dunnett SB, Ferrante RJ, Albin R, Shelbourne P, Delorenzi M, Augood SJ, Faull RL, Olson JM, Bates GP, Jones L, and Luthi-Carter R
- Subjects
- Animals, Brain metabolism, Brain pathology, Disease Models, Animal, Gene Dosage, Humans, Huntingtin Protein, Huntington Disease metabolism, Huntington Disease pathology, Mice, Mice, Mutant Strains, Nerve Tissue Proteins metabolism, Neurons metabolism, Nuclear Proteins metabolism, Phenotype, RNA, Messenger metabolism, Corpus Striatum metabolism, Gene Expression, Huntington Disease genetics, Mutation, Nerve Tissue Proteins genetics, Nuclear Proteins genetics
- Abstract
To test the hypotheses that mutant huntingtin protein length and wild-type huntingtin dosage have important effects on disease-related transcriptional dysfunction, we compared the changes in mRNA in seven genetic mouse models of Huntington's disease (HD) and postmortem human HD caudate. Transgenic models expressing short N-terminal fragments of mutant huntingtin (R6/1 and R6/2 mice) exhibited the most rapid effects on gene expression, consistent with previous studies. Although changes in the brains of knock-in and full-length transgenic models of HD took longer to appear, 15- and 22-month CHL2(Q150/Q150), 18-month Hdh(Q92/Q92) and 2-year-old YAC128 animals also exhibited significant HD-like mRNA signatures. Whereas it was expected that the expression of full-length huntingtin transprotein might result in unique gene expression changes compared with those caused by the expression of an N-terminal huntingtin fragment, no discernable differences between full-length and fragment models were detected. In addition, very high correlations between the signatures of mice expressing normal levels of wild-type huntingtin and mice in which the wild-type protein is absent suggest a limited effect of the wild-type protein to change basal gene expression or to influence the qualitative disease-related effect of mutant huntingtin. The combined analysis of mouse and human HD transcriptomes provides important temporal and mechanistic insights into the process by which mutant huntingtin kills striatal neurons. In addition, the discovery that several available lines of HD mice faithfully recapitulate the gene expression signature of the human disorder provides a novel aspect of validation with respect to their use in preclinical therapeutic trials.
- Published
- 2007
- Full Text
- View/download PDF
44. Nortriptyline delays disease onset in models of chronic neurodegeneration.
- Author
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Wang H, Guan Y, Wang X, Smith K, Cormier K, Zhu S, Stavrovskaya IG, Huo C, Ferrante RJ, Kristal BS, and Friedlander RM
- Subjects
- Amyotrophic Lateral Sclerosis drug therapy, Amyotrophic Lateral Sclerosis metabolism, Amyotrophic Lateral Sclerosis physiopathology, Animals, Antidepressive Agents, Tricyclic pharmacology, Apoptosis drug effects, Apoptosis physiology, Brain metabolism, Brain physiopathology, Chronic Disease, Disease Models, Animal, Disease Progression, Humans, Huntington Disease drug therapy, Huntington Disease metabolism, Huntington Disease physiopathology, Male, Membrane Potential, Mitochondrial drug effects, Membrane Potential, Mitochondrial physiology, Mice, Mice, Transgenic, Mitochondria metabolism, Neurodegenerative Diseases metabolism, Neurodegenerative Diseases physiopathology, Neurons metabolism, Time Factors, Treatment Outcome, Brain drug effects, Mitochondria drug effects, Neurodegenerative Diseases drug therapy, Neurons drug effects, Neuroprotective Agents pharmacology, Nortriptyline pharmacology
- Abstract
This study was to characterize the neuroprotective effects of nortriptyline, a tricyclic antidepressant, in mouse models of chronic neurodegeneration [amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD)]. Nortriptyline was originally selected from a library screening of 1040 FDA-approved drugs by using isolated mitochondria. It emerged as a strong inhibitor of mitochondrial permeability transition (mPT). Our results showed that nortriptyline significantly delayed disease onset and extended the lifespan of ALS mice although its effect on mortality was less than that on onset. We also tested promethazine, another compound which emerged from the same screening, in ALS mice. Promethazine-treated ALS mice exhibited a significant delay in disease onset but not in mortality. Histochemistry analysis found that nortriptyline treatment indeed protected motor neurons from death and reduced ventral horn atrophy in ALS mice. Furthermore, release of cytochrome c and activation of caspase 3, two molecular phenomena associated with mitochondrial-pathway-mediated cell death, were inhibited by nortriptyline. We also demonstrated similar beneficial effects of nortriptyline in HD mice: it extended the presymptomatic portion of the disease but had no effect on mortality. In an established cellular model of HD, nortriptyline inhibited cell death and decreased loss of mitochondrial membrane potential. In summary, this study indicated the potential therapeutic usefulness of nortriptyline in ALS and HD. In addition, our data suggested a role for mPT in chronic neurodegeneration, particularly at the early rather than the advanced disease stages.
- Published
- 2007
- Full Text
- View/download PDF
45. Mutant SOD1G93A in bone marrow-derived cells exacerbates 3-nitropropionic acid induced striatal damage in mice.
- Author
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Huang QY, Yu L, Ferrante RJ, and Chen JF
- Subjects
- Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis metabolism, Amyotrophic Lateral Sclerosis physiopathology, Animals, Bone Marrow Cells enzymology, Bone Marrow Transplantation, Corpus Striatum physiopathology, Genetic Predisposition to Disease genetics, Humans, Huntington Disease chemically induced, Huntington Disease enzymology, Huntington Disease genetics, Injections, Intraperitoneal adverse effects, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mutation genetics, Nerve Degeneration physiopathology, Neurotoxins, Oxidative Stress genetics, Superoxide Dismutase-1, Transplantation Chimera, Corpus Striatum drug effects, Corpus Striatum metabolism, Nerve Degeneration chemically induced, Nerve Degeneration genetics, Nitro Compounds toxicity, Propionates toxicity, Superoxide Dismutase genetics
- Abstract
3-Nitropropionic acid (3-NP), an irreversible inhibitor of succinate dehydrogenase, produces selective lesions in striatal neurons that resemble those observed in Huntington's disease neuropathology. In this study, we evaluated the role of peripheral bone marrow-derived cells (BMDCs) in the 3-NP-induced striatal damage by transplanting bone marrow cells with human SOD1 G93A mutation (mSOD1(G93A)) which induces amyotrophic lateral sclerosis through an unknown gain of toxicity and mitochondrial dysfunction. We assessed striatal damage after 3-NP treatment in the recipient C57BL/6 wild-type (WT) mice that received bone marrow cells from WT or mSOD1(G93A) transgenic donor mice (WT-->WT or mSOD(G93A)-->WT). After intraperitoneal injection of 3-NP, six of the eight mSOD1(G93A)-->WT mice had bilateral striatal lesions while only one out of eight WT-->WT mice had a striatal lesion. The lesion volume was significantly higher in the mSOD1(G93A)-->WT mice than in the WT-->WT mice. However, following an intrastriatal injection of 3-NP, there was no significant difference in the lesion volumes between the WT-->WT mice and mSOD1(G93A)-->WT mice. Thus, the exacerbation of 3-NP-induced striatal damage in mSOD(G93A)-->WT mice was only seen after systemic administration of 3-NP, but not after intrastriatal injection. These results demonstrate that altered SOD1 activity (mSOD(G93A)) in BMDCs affects striatal damage probably through a mechanism involving a systemic factor.
- Published
- 2007
- Full Text
- View/download PDF
46. Modulation of nucleosome dynamics in Huntington's disease.
- Author
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Stack EC, Del Signore SJ, Luthi-Carter R, Soh BY, Goldstein DR, Matson S, Goodrich S, Markey AL, Cormier K, Hagerty SW, Smith K, Ryu H, and Ferrante RJ
- Subjects
- Acetylation, Animals, Brain drug effects, Brain pathology, Chromomycins pharmacology, Disease Models, Animal, Female, Histones metabolism, Humans, Huntingtin Protein, Huntington Disease drug therapy, Huntington Disease pathology, Huntington Disease physiopathology, Methylation, Mice, Mice, Inbred CBA, Mice, Transgenic, Motor Activity drug effects, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Nuclear Proteins genetics, Nuclear Proteins metabolism, Nucleosomes drug effects, Plicamycin pharmacology, Transcription, Genetic drug effects, Huntington Disease genetics, Huntington Disease metabolism, Nucleosomes metabolism
- Abstract
Transcriptional dysregulation and aberrant chromatin remodeling are central features in the pathology of Huntington's disease (HD). In order to more fully characterize these pathogenic events, an assessment of histone profiles and associated gene changes were performed in transgenic N171-82Q (82Q) and R6/2 HD mice. Analyses revealed significant chromatin modification, resulting in reduced histone acetylation with concomitant increased histone methylation, consistent with findings observed in HD patients. While there are no known interventions that ameliorate or arrest HD progression, DNA/RNA-binding anthracyclines may provide significant therapeutic potential by correcting pathological nucleosome changes and realigning transcription. Two such anthracyclines, chromomycin and mithramycin, improved altered nucleosome homeostasis in HD mice, normalizing the chromatin pattern. There was a significant shift in the balance between methylation and acetylation in treated HD mice to that found in wild-type mice, resulting in greater acetylation of histone H3 at lysine 9 and promoting gene transcription. Gene expression profiling in anthracycline-treated HD mice showed molecular changes that correlate with disease correction, such that a subset of downregulated genes were upregulated with anthracycline treatment. Improved nucleosomal dynamics were concurrent with a significant improvement in the behavioral and neuropathological phenotype observed in HD mice. These data show the ability of anthracycline compounds to rebalance epigenetic histone modification and, as such, may provide the rationale for the design of human clinical trials in HD patients.
- Published
- 2007
- Full Text
- View/download PDF
47. Conformation-sensitive antibodies against alzheimer amyloid-beta by immunization with a thioredoxin-constrained B-cell epitope peptide.
- Author
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Moretto N, Bolchi A, Rivetti C, Imbimbo BP, Villetti G, Pietrini V, Polonelli L, Del Signore S, Smith KM, Ferrante RJ, and Ottonello S
- Subjects
- Alzheimer Disease metabolism, Alzheimer Disease pathology, Amyloid beta-Peptides chemistry, Amyloid beta-Peptides metabolism, Animals, Brain metabolism, Brain pathology, Humans, Male, Mice, Mice, Inbred BALB C, Mice, Transgenic, Models, Molecular, Protein Structure, Tertiary, Recombinant Proteins chemistry, Recombinant Proteins immunology, Recombinant Proteins metabolism, Thioredoxins chemistry, Thioredoxins metabolism, Alzheimer Disease immunology, Amyloid beta-Peptides immunology, Antibodies immunology, Epitopes, B-Lymphocyte immunology, Peptide Fragments immunology, Thioredoxins immunology
- Abstract
Immunotherapy against the amyloid-beta (Abeta) peptide is a valuable potential treatment for Alzheimer disease (AD). An ideal antigen should be soluble and nontoxic, avoid the C-terminally located T-cell epitope of Abeta, and yet be capable of eliciting antibodies that recognize Abeta fibrils and neurotoxic Abeta oligomers but not the physiological monomeric species of Abeta. We have described here the construction and immunological characterization of a recombinant antigen with these features obtained by tandem multimerization of the immunodominant B-cell epitope peptide Abeta1-15 (Abeta15) within the active site loop of bacterial thioredoxin (Trx). Chimeric Trx(Abeta15)n polypeptides bearing one, four, or eight copies of Abeta15 were constructed and injected into mice in combination with alum, an adjuvant approved for human use. All three polypeptides were found to be immunogenic, yet eliciting antibodies with distinct recognition specificities. The anti-Trx(Abeta15)4 antibody, in particular, recognized Abeta42 fibrils and oligomers but not monomers and exhibited the same kind of conformational selectivity against transthyretin, an amyloidogenic protein unrelated in sequence to Abeta. We have also demonstrated that anti-Trx(Abeta15)4, which binds to human AD plaques, markedly reduces Abeta pathology in transgenic AD mice. The data indicate that a conformational epitope shared by oligomers and fibrils can be mimicked by a thioredoxin-constrained Abeta fragment repeat and identify Trx(Abeta15)4 as a promising new tool for AD immunotherapy.
- Published
- 2007
- Full Text
- View/download PDF
48. Translational therapeutic strategies in amyotrophic lateral sclerosis.
- Author
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Ryu H and Ferrante RJ
- Subjects
- Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis metabolism, Amyotrophic Lateral Sclerosis pathology, Animals, Disease Models, Animal, Humans, Mitochondrial Diseases drug therapy, Mitochondrial Diseases metabolism, Oxidative Stress, Signal Transduction, Transcription, Genetic genetics, Amyotrophic Lateral Sclerosis drug therapy
- Abstract
Amyotrophic lateral sclerosis (ALS) is a clinically severe and fatal neurodegenerative disease characterized by a loss of both upper and lower motor neurons, resulting in progressive muscle loss and paralysis. While the exact cause of neuronal death in ALS remains unknown, it is proposed that multiple molecular defects trigger motor neuron cell death. These pathophysiological mechanisms include oxidative stress, mitochondrial impairment, protein aggregation, glutamate cytotoxicity, transcription dysfunction, inflammation, and apoptotic cell death. An understanding of how these potential therapeutic targets interrelate will provide direction both in the development of a pharmacotherapy and in the design of clinical trials in ALS. Important issues related to therapeutic development are the principals that should be followed in designing and conducting experiments using genetic animal models and what body of evidence is desirable to fully inform clinical decision making. In the context of ALS, we review some of the salient issues related to the use of genetic models in providing a guide to assessing studies in translating therapeutic strategies to patients with ALS and discuss therapeutic targets and pharmacological approaches to slowing disease progression. As in other neurodegenerative diseases, the most effective neuroprotection may result from combined treatment strategies.
- Published
- 2007
- Full Text
- View/download PDF
49. The neuroprotective role of creatine.
- Author
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Klein AM and Ferrante RJ
- Subjects
- Acute Disease, Adenosine Triphosphate metabolism, Animals, Cell Death drug effects, Chronic Disease, Creatine metabolism, Disease Models, Animal, Humans, Neurodegenerative Diseases metabolism, Neurons metabolism, Neuroprotective Agents metabolism, Creatine therapeutic use, Energy Metabolism drug effects, Homeostasis drug effects, Neurodegenerative Diseases drug therapy, Neuroprotective Agents therapeutic use
- Abstract
Significant progress has been made in identifying neuroprotective agents and their translation to patients with neurological disorders. While the direct causative pathways of neurodegeneration remain unclear, they are under great clinical and experimental investigation. There are a number of interrelated pathogenic mechanisms triggering molecular events that lead to neuronal death. One putative mechanism reported to play a prominent role in the pathogenesis of neurological diseases is impaired energy metabolism. If reduced energy stores play a role in neuronal loss, then therapeutic strategies that buffer intracellular energy levels may prevent or impede the neurodegenerative process. Recent studies suggest that impaired energy production promotes neurological disease onset and progression. Sustained ATP levels are critical to cellular homeostasis and may have both direct and indirect influence on pathogenic mechanisms associated with neurological disorders. Creatine is a critical component in maintaining cellular energy homeostasis, and its administration has been reported to be neuroprotective in a wide number of both acute and chronic experimental models of neurological disease. In the context of this chapter, we will review the experimental evidence for creatine supplementation as a neurotherapeutic strategy in patients with neurological disorders, including Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Alzheimer's disease, as well as in ischemic stroke, brain and spinal cord trauma, and epilepsy.
- Published
- 2007
- Full Text
- View/download PDF
50. ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in Huntington's disease.
- Author
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Ryu H, Lee J, Hagerty SW, Soh BY, McAlpin SE, Cormier KA, Smith KM, and Ferrante RJ
- Subjects
- Aged, Animals, Cystamine therapeutic use, Female, Histone-Lysine N-Methyltransferase, Humans, Huntington Disease drug therapy, Huntington Disease genetics, Huntington Disease pathology, Male, Methylation, Mice, Middle Aged, Phenotype, Plicamycin therapeutic use, Promoter Regions, Genetic genetics, Protein Methyltransferases genetics, Sp3 Transcription Factor metabolism, Survival Rate, Up-Regulation, Gene Expression drug effects, Histones metabolism, Huntington Disease metabolism, Protein Methyltransferases metabolism
- Abstract
Chromatin remodeling and transcription regulation are tightly controlled under physiological conditions. It has been suggested that altered chromatin modulation and transcription dysfunction may play a role in the pathogenesis of Huntington's disease (HD). Increased histone methylation, a well established mechanism of gene silencing, results in transcriptional repression. ERG-associated protein with SET domain (ESET), a histone H3 (K9) methyltransferase, mediates histone methylation. We show that ESET expression is markedly increased in HD patients and in transgenic R6/2 HD mice. Similarly, the protein level of trimethylated histone H3 (K9) was also elevated in HD patients and in R6/2 mice. We further demonstrate that both specificity protein 1 (Sp1) and specificity protein 3 (Sp3) act as transcriptional activators of the ESET promoter in neurons and that mithramycin, a clinically approved guanosine-cytosine-rich DNA binding antitumor antibiotic, interferes with the DNA binding of these Sp family transcription factors, suppressing basal ESET promoter activity in a dose dependent manner. The combined pharmacological treatment with mithramycin and cystamine down-regulates ESET gene expression and reduces hypertrimethylation of histone H3 (K9). This polytherapy significantly ameliorated the behavioral and neuropathological phenotype in the R6/2 mice and extended survival over 40%, well beyond any existing reported treatment in HD mice. Our data suggest that modulation of gene silencing mechanisms, through regulation of the ESET gene is important to neuronal survival and, as such, may be a promising treatment in HD patients.
- Published
- 2006
- Full Text
- View/download PDF
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