14 results on '"Miranda, Helen C."'
Search Results
2. Skeletal muscle TFEB signaling promotes central nervous system function and reduces neuroinflammation during aging and neurodegenerative disease
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Matthews, Ian, Birnbaum, Allison, Gromova, Anastasia, Huang, Amy W., Liu, Kailin, Liu, Eleanor A., Coutinho, Kristen, McGraw, Megan, Patterson, Dalton C., Banks, Macy T., Nobles, Amber C., Nguyen, Nhat, Merrihew, Gennifer E., Wang, Lu, Baeuerle, Eric, Fernandez, Elizabeth, Musi, Nicolas, MacCoss, Michael J., Miranda, Helen C., La Spada, Albert R., and Cortes, Constanza J.
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- 2023
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3. Selective modulation of the androgen receptor AF2 domain rescues degeneration in spinal bulbar muscular atrophy
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Badders, Nisha M, Korff, Ane, Miranda, Helen C, Vuppala, Pradeep K, Smith, Rebecca B, Winborn, Brett J, Quemin, Emmanuelle R, Sopher, Bryce L, Dearman, Jennifer, Messing, James, Kim, Nam Chul, Moore, Jennifer, Freibaum, Brian D, Kanagaraj, Anderson P, Fan, Baochang, Tillman, Heather, Chen, Ping-Chung, Wang, Yingzhe, III, Burgess B Freeman, Li, Yimei, Kim, Hong Joo, La Spada, Albert R, and Taylor, J Paul
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Biological response modifiers -- Physiological aspects -- Health aspects ,Kennedy disease -- Development and progression -- Genetic aspects -- Care and treatment ,Hormone receptors -- Genetic aspects -- Health aspects ,Muscular atrophy -- Analysis -- Physiological aspects -- Care and treatment ,Androgens -- Physiological aspects -- Health aspects ,Biological sciences ,Health - Abstract
Spinal bulbar muscular atrophy (SBMA) is a motor neuron disease caused by toxic gain of function of the androgen receptor (AR). Previously, we found that co-regulator binding through the activation function-2 (AF2) domain of AR is essential for pathogenesis, suggesting that AF2 may be a potential drug target for selective modulation of toxic AR activity. We screened previously identified AF2 modulators for their ability to rescue toxicity in a Drosophila model of SBMA. We identified two compounds, tolfenamic acid (TA) and 1-[2-(4-methylphenoxy)ethyl]-2-[(2-phenoxyethyl)sulfanyl]-1H-benzimidazole (MEPB), as top candidates for rescuing lethality, locomotor function and neuromuscular junction defects in SBMA flies. Pharmacokinetic analyses in mice revealed a more favorable bioavailability and tissue retention of MEPB compared with TA in muscle, brain and spinal cord. In a preclinical trial in a new mouse model of SBMA, MEPB treatment yielded a dose-dependent rescue from loss of body weight, rotarod activity and grip strength. In addition, MEPB ameliorated neuronal loss, neurogenic atrophy and testicular atrophy, validating AF2 modulation as a potent androgen-sparing strategy for SBMA therapy., Author(s): Nisha M Badders [1]; Ane Korff [1, 2]; Helen C Miranda [3]; Pradeep K Vuppala [4]; Rebecca B Smith [1]; Brett J Winborn [1]; Emmanuelle R Quemin [1]; Bryce [...]
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- 2018
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4. Generation of advanced cerebellar organoids for neurogenesis and neuronal network development.
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Chen, Ya, Bury, Luke A, Chen, Fu, Aldinger, Kimberly A, Miranda, Helen C, and Wynshaw-Boris, Anthony
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- 2023
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5. PPAR-δ is repressed in Huntington's disease, is required for normal neuronal function and can be targeted therapeutically
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Dickey, Audrey S., Pineda, Victor V., Tsunemi, Taiji, Liu, Patrick P., Miranda, Helen C., Gilmore-Hall, Stephen K., Lomas, Nicole, Sampat, Kunal R., Buttgereit, Anne, Torres, Mark-Joseph Manalang, Flores, April L., Arreola, Martin, Arbez, Nicolas, Akimov, Sergey S., Gaasterland, Terry, Lazarowski, Eduardo R., Ross, Christopher A., Yeo, Gene W., Sopher, Bryce L., Magnuson, Gavin K., Pinkerton, Anthony B., Masliah, Eliezer, and La Spada, Albert R.
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Neural receptors -- Physiological aspects -- Genetic aspects -- Research ,Huntington's chorea -- Development and progression -- Genetic aspects -- Research ,Biological sciences ,Health - Abstract
Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene, which encodes a polyglutamine tract in the HTT protein. We found that peroxisome proliferator- activated receptor delta (PPAR-δ) interacts with HTT and that mutant HTT represses PPAR-δ-mediated transactivation. Increased PPAR-δ transactivation ameliorated mitochondrial dysfunction and improved cell survival of neurons from mouse models of HD. Expression of dominant-negative PPAR-δ in the central nervous system of mice was sufficient to induce motor dysfunction, neurodegeneration, mitochondrial abnormalities and transcriptional alterations that recapitulated HD-like phenotypes. Expression of dominant-negative PPAR-δ specifically in the striatum of medium spiny neurons in mice yielded HD- like motor phenotypes, accompanied by striatal neuron loss. In mouse models of HD, pharmacologic activation of PPAR-δ using the agonist KD3010 improved motor function, reduced neurodegeneration and increased survival. PPAR-δ activation also reduced HTT-induced neurotoxicity in vitro and in medium spiny-like neurons generated from stem cells derived from individuals with HD, indicating that PPAR-δ activation may be beneficial in HD and related disorders., The PPARs are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. The three subtypes--termed PPAR-α, PPAR-δ and PPAR-γ--serve as lipid sensors in response to increased energy requirements [...]
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- 2016
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6. Multiplexed microfluidic chip for cell co-culture.
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Watson, Craig, Liu, Chao, Ansari, Ali, Miranda, Helen C., Somoza, Rodrigo A., and Senyo, Samuel E.
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CELL culture ,CELL survival ,CELL communication ,VALVES ,IMMUNOCYTOCHEMISTRY ,IN vitro studies - Abstract
Paracrine signaling is challenging to study in vitro, as conventional culture tools dilute soluble factors and offer little to no spatiotemporal control over signaling. Microfluidic chips offer potential to address both of these issues. However, few solutions offer both control over onset and duration of cell–cell communication, and high throughput. We have developed a microfluidic chip designed to culture cells in adjacent chambers, separated by valves to selectively allow or prevent exchange of paracrine signals. The chip features 16 fluidic inputs and 128 individually-addressable chambers arranged in 32 sets of 4 chambers. Media can be continuously perfused or delivered by diffusion, which we model under different culture conditions to ensure normal cell viability. Immunocytochemistry assays can be performed in the chip, which we modeled and fine-tuned to reduce total assay time to 1 h. Finally, we validate the use of the chip for co-culture studies by showing that HEK293Ta cells respond to signals secreted by RAW 264.7 immune cells in adjacent chambers, only when the valve between the chambers is opened. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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7. An epilepsy‐associated ACTL6B variant captures neuronal hyperexcitability in a human induced pluripotent stem cell model.
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Ahn, Lucie Y., Coatti, Giuliana C., Liu, Jingyi, Gumus, Evren, Schaffer, Ashleigh E., and Miranda, Helen C.
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- 2021
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8. Direct Generation of Human Cortical Organoids from Primary Cells.
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Schukking, Monique, Miranda, Helen C., Trujillo, Cleber A., Negraes, Priscilla D., and Muotri, Alysson R.
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ORGANOIDS , *PLURIPOTENT stem cells , *NEURAL development , *NEURODEVELOPMENTAL treatment , *GENE expression - Abstract
The study of variations in human neurodevelopment and cognition is limited by the availability of experimental models. While animal models only partially recapitulate the human brain development, genetics, and heterogeneity, human-induced pluripotent stem cells can provide an attractive experimental alternative. However, cellular reprogramming and further differentiation techniques are costly and time-consuming and therefore, studies using this approach are often limited to a small number of samples. In this study, we describe a rapid and cost-effective method to reprogram somatic cells and the direct generation of cortical organoids in a 96-well format. Our data are a proof-of-principle that a large cohort of samples can be generated for experimental assessment of the human neural development. [ABSTRACT FROM AUTHOR]
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- 2018
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9. Adenylyl cyclase activating polypeptide reduces phosphorylation and toxicity of the polyglutamine-expanded androgen receptor in spinobulbar muscular atrophy.
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Polanco, Maria Josè, Parodi, Sara, Piol, Diana, Stack, Conor, Chivet, Mathilde, Contestabile, Andrea, Miranda, Helen C., Lievens, Patricia M.-J., Espinoza, Stefano, Jochum, Tobias, Rocchi, Anna, Grunseich, Christopher, Gainetdinov, Raul R., Cato, Andrew C. B., Lieberman, Andrew P., La Spada, Albert R., Sambataro, Fabio, Fischbeck, Kenneth H., Gozes, Illana, and Pennuto, Maria
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POLYGLUTAMINE ,ANDROGEN receptors ,PHOSPHORYLATION ,PROTEIN kinases ,JAK-STAT pathway - Abstract
This article presents a study on the development of a strategy to reduce polyglutamine-androgen receptor(AR) (polyQ-AR) accumulation and toxicity in degenerating cells by modulation of the AR phosphorylation state. It discusses a decrease in the accumulation of phosphorylated AR in neuronal cells by adenylyl cyclase/protein kinase A signaling pathway, and the effect of phosphorylation on aggregation and turnover of polyQ-AR.
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- 2016
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10. Nemo-like kinase is a novel regulator of spinal and bulbar muscular atrophy.
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Todd, Tiffany W., Hiroshi Kokubu, Miranda, Helen C., Cortes, Constanza J., Spada, Albert R. La, and Janghoo Lim
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MUSCULAR atrophy ,KINASES ,SPINE diseases - Abstract
The article discusses a study which shows the promotion of disease pathogenesis in spinal and bulbar muscular atrophy (SBMA) model systems by nemo-like kinase (NLK).
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- 2015
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11. Polyglutamine-expanded androgen receptor interferes with TFEB to elicit autophagy defects in SBMA.
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Cortes, Constanza J, Miranda, Helen C, Frankowski, Harald, Batlevi, Yakup, Young, Jessica E, Le, Amy, Ivanov, Nishi, Sopher, Bryce L, Carromeu, Cassiano, Muotri, Alysson R, Garden, Gwenn A, and La Spada, Albert R
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POLYGLUTAMINE , *GLUTAMINE , *STEROID receptors , *ANDROGEN receptors , *NEURONS - Abstract
Macroautophagy (hereafter autophagy) is a key pathway in neurodegeneration. Despite protective actions, autophagy may contribute to neuron demise when dysregulated. Here we consider X-linked spinal and bulbar muscular atrophy (SBMA), a repeat disorder caused by polyglutamine-expanded androgen receptor (polyQ-AR). We found that polyQ-AR reduced long-term protein turnover and impaired autophagic flux in motor neuron-like cells. Ultrastructural analysis of SBMA mice revealed a block in autophagy pathway progression. We examined the transcriptional regulation of autophagy and observed a functionally significant physical interaction between transcription factor EB (TFEB) and AR. Normal AR promoted, but polyQ-AR interfered with, TFEB transactivation. To evaluate physiological relevance, we reprogrammed patient fibroblasts to induced pluripotent stem cells and then to neuronal precursor cells (NPCs). We compared multiple SBMA NPC lines and documented the metabolic and autophagic flux defects that could be rescued by TFEB. Our results indicate that polyQ-AR diminishes TFEB function to impair autophagy and promote SBMA pathogenesis. [ABSTRACT FROM AUTHOR]
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- 2014
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12. Implications of mRNA translation dysregulation for neurological disorders.
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Jishi, Aya, Qi, Xin, and Miranda, Helen C.
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NEUROLOGICAL disorders , *FRAGILE X syndrome , *AUTISM spectrum disorders , *CELL survival , *GENETIC translation - Abstract
The translation of information encoded in the DNA into functional proteins is one of the tenets of cellular biology. Cell survival and function depend on the tightly controlled processes of transcription and translation. Growing evidence suggests that dysregulation in mRNA translation plays an important role in the pathogenesis of several neurodevelopmental diseases, such as autism spectrum disorder (ASD) and fragile X syndrome (FXS) as well as neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). In this review, we provide an overview of mRNA translation and its modes of regulation that have been implicated in neurological disease. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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13. Suppression of premature transcription termination leads to reduced mRNA isoform diversity and neurodegeneration.
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LaForce, Geneva R., Farr, Jordan S., Liu, Jingyi, Akesson, Cydni, Gumus, Evren, Pinkard, Otis, Miranda, Helen C., Johnson, Katherine, Sweet, Thomas J., Ji, Ping, Lin, Ai, Coller, Jeff, Philippidou, Polyxeni, Wagner, Eric J., and Schaffer, Ashleigh E.
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MOTOR neuron diseases , *MESSENGER RNA , *GENETIC overexpression , *RNA regulation , *MOTOR neurons - Abstract
Tight regulation of mRNA isoform expression is essential for neuronal development, maintenance, and function; however, the repertoire of proteins that govern isoform composition and abundance remains incomplete. Here, we show that the RNA kinase CLP1 regulates mRNA isoform expression through suppression of proximal cleavage and polyadenylation. We found that human stem-cell-derived motor neurons without CLP1 or with the disease-associated CLP1 p.R140H variant had distinct patterns of RNA-polymerase-II-associated cleavage and polyadenylation complex proteins that correlated with polyadenylation site usage. These changes resulted in imbalanced mRNA isoform expression of long genes important for neuronal function that were recapitulated in vivo. Strikingly, we observed the same pattern of reduced mRNA isoform diversity in 3′ end sequencing data from brain tissues of patients with neurodegenerative disease. Together, our results identify a previously uncharacterized role for CLP1 in mRNA 3′ end formation and reveal an mRNA misprocessing signature in neurodegeneration that may suggest a common mechanism of disease. [Display omitted] • CLP1 limits mRNA isoform diversity by suppressing proximal poly(A) site choice • CLP1 knockout and pathogenic CLP1 p.R140H have opposing effects on mRNA processing • Intronic polyadenylation evasion drives overexpression of long genes in neurons • Neurodegenerative diseases show a pattern of reduced mRNA 3′ end diversity LaForce et al. utilize motor neuron disease models to examine CLP1 function in mRNA 3′ end formation. CLP1 suppresses proximal polyadenylation to regulate mRNA isoform balance and maintain neuronal health. The authors find that diminished isoform diversity is a signature of neurodegenerative disease. [ABSTRACT FROM AUTHOR]
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- 2022
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14. Scalable, optically-responsive human neuromuscular junction model reveals convergent mechanisms of synaptic dysfunction in familial ALS.
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Chen D, Philippidou P, Brenha BF, Schaffer AE, and Miranda HC
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Neuromuscular junctions (NMJs) are specialized synapses that mediate communication between motor neurons and skeletal muscles and are essential for movement. The degeneration of this system can lead to symptoms observed in neuromuscular and motor neuron diseases. Studying these synapses and their degeneration has proven challenging. Prior NMJ studies heavily relied upon the use of mouse, chick, or isolated primary human cells, which have demonstrated limited fidelity for disease modeling. To enable the study of NMJ dysfunction and model genetic diseases, we, and others, have developed methods to generate human NMJs from pluripotent stem cells (PSCs), embryonic stem cells, and induced pluripotent stem cells. However, published studies have highlighted technical limitations associated with these complex in vitro NMJ models. In this study, we developed a robust PSC-derived motor neuron and skeletal muscle co-culture method, and demonstrated its sensitivity in modeling motor neuron disease. Our method spontaneously and reproducibly forms human NMJs. We developed multiwell-multielectrode array (MEA) parameters to quantify the activity of PSC-derived skeletal muscles, as well as measured the electrophysiological activity of functional human PSC-derived NMJs. We further leveraged our method to morphologically and functionally assess NMJs from the familial amyotrophic lateral sclerosis (fALS) PSCs, C9orf72 hexanucleotide (G4C2)n repeat expansion (HRE), SOD1
A5V , and TDP43G298S to define the reproducibility and sensitivity of our system. We observed a significant decrease in the numbers and activity of PSC-derived NMJs developed from the different ALS lines compared to their respective controls. Furthermore, we evaluated a therapeutic candidate undergoing clinical trials and observed a variant-dependent rescue of functionality of NMJs. Our newly developed method provides a platform for the systematic investigation of genetic causes of NMJ neurodegeneration and highlights the need for therapeutic avenues to consider patient genotype.- Published
- 2024
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