20 results on '"Naranian, T."'
Search Results
2. A144 A MULTIDISCIPLINARY TEAM APPROACH REDUCES PEG SITE COMPLICATIONS
- Author
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Truax, A M, primary, Reardon, J, primary, Naranian, T, primary, and Liu, L W, primary
- Published
- 2020
- Full Text
- View/download PDF
3. Stress and distress in parents of neonates admitted to the neonatal intensive care unit for cardiac surgery
- Author
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Diffin, J., primary, Spence, K., additional, Naranian, T., additional, Badawi, N., additional, and Johnston, L., additional
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- 2016
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4. Mcl-1 is a key regulator of the ovarian reserve
- Author
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Omari, S, primary, Waters, M, additional, Naranian, T, additional, Kim, K, additional, Perumalsamy, A L, additional, Chi, M, additional, Greenblatt, E, additional, Moley, K H, additional, Opferman, J T, additional, and Jurisicova, A, additional
- Published
- 2015
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5. Enhancing Self-Management of Percutaneous Endoscopic Gastrostomy Tubes Through the Implementation of a Standardized Education and Assessment Pathway: A Quality Improvement Initiative.
- Author
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Reardon J, Truax AE, Naranian T, and Liu LWC
- Subjects
- Humans, Antiparkinson Agents adverse effects, Gastrostomy adverse effects, Gastrostomy methods, Retrospective Studies, Quality Improvement, Parkinson Disease, Self-Management
- Abstract
Intraduodenal infusion of levodopa-carbidopa intestinal gel by percutaneous endoscopic gastrostomy tube with jejunal extension is a treatment option to reduce motor and nonmotor complications in patients with advanced Parkinson's disease when oral therapy no longer provides sufficient benefit. Medication management is of central focus; however, there was no standardized patient education on stoma-site care and tube maintenance, leading to the development of stoma-site complications. As a quality improvement (QI) initiative, a standardized education and assessment pathway was developed and implemented in an urban academic outpatient clinic to enhance patient self-management and reduce stoma-site complications. A retrospective chart review was conducted to establish baseline incidence of cutaneous stoma-site complications. QI interventions were implemented using a rapid-cycle improvement model. Routine stoma assessments by a nurse who specializes in wound, ostomy, and continence care were implemented at set points, and patient education on PEG tube care and maintenance was reinforced at each session. Results demonstrated a significant reduction in moderate-to-severe tube and stoma-site-related complication. Implementation of a similar standardized education and assessment pathway in patients with percutaneous endoscopic gastrostomy tubes may lead to a decrease in stoma-site-related complications and overall better patient self-management., (Copyright © 2023 Society of Gastroenterology Nurses and Associates.)
- Published
- 2023
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6. Vitamins and Infusion of Levodopa-Carbidopa Intestinal Gel.
- Author
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Taher J, Naranian T, Poon YY, Merola A, Mestre T, Suchowersky O, Kulasingam V, and Fasano A
- Subjects
- Antiparkinson Agents adverse effects, Humans, Quality of Life, Vitamins therapeutic use, Carbidopa, Levodopa adverse effects
- Abstract
Levodopa-carbidopa intestinal gel infusion (LCIG) is an established therapy for advanced Parkinson disease (PD), resulting in a significant improvement of quality of life. With increased LCIG adoption worldwide, potential complications due to abnormal vitamin absorption or metabolism have been reported in these patients. Neurologists are unfamiliar with vitamins physiology and pathophysiological mechanisms in case of their deficiency. Unfortunately, clinical and laboratory guidelines related to vitamin monitoring and supplementation in the context of treatment with LCIG are not available. We herein summarize the current knowledge on three vitamins that are reduced with LCIG therapy reporting on their physiology, laboratory testing, and clinical impact of their deficiency/excess. In addition, we proposed an opinion-based recommendation for clinicians treating LCIG patients. Patients and caregivers should be informed about the risk of vitamin deficiency. Vitamin B12, homocysteine, and methylmalonic acid (MMA) should be tested before starting LCIG, six months after and once/year thereafter. Vitamin B6 and folate testing is not universally available but it should be considered if homocysteine is elevated but MMA and/or total vitamin B12 are normal. Prophylaxis of vitamin deficiency should be started as soon as LCIG is implemented, possibly even before. Dietary recommendations are enough in most patients although a subgroup of patients is at higher risk and should receive Vitamin B12 regularly and cycles of B6. Finally, once diagnosed a vitamin deficiency should be readily treated and accompanied by clinical and laboratory monitoring. Resistant cases should receive non-oral routes of administration and possibly discontinue LCIG, even temporarily.
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- 2022
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7. Axial Impairment Following Deep Brain Stimulation in Parkinson's Disease: A Surgicogenomic Approach.
- Author
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Visanji NP, Ghani M, Yu E, Kakhki EG, Sato C, Moreno D, Naranian T, Poon YY, Abdollahi M, Naghibzadeh M, Rajalingam R, Lozano AM, Kalia SK, Hodaie M, Cohn M, Statucka M, Boutet A, Elias GJB, Germann J, Munhoz R, Lang AE, Gan-Or Z, Rogaeva E, and Fasano A
- Subjects
- Humans, Levodopa, Retrospective Studies, Treatment Outcome, Trypsin, Deep Brain Stimulation adverse effects, Deep Brain Stimulation methods, Parkinson Disease complications, Parkinson Disease genetics, Parkinson Disease therapy
- Abstract
Background: Postoperative outcome following deep brain stimulation (DBS) of the subthalamic nucleus is variable, particularly with respect to axial motor improvement. We hypothesized a genetic underpinning to the response to surgical intervention, termed "surgicogenomics"., Objective: We aimed to identify genetic variants associated with clinical heterogeneity in DBS outcome of Parkinson's disease (PD) patients that could then be applied clinically to target selection leading to improved surgical outcome., Methods: Retrospective clinical data was extracted from 150 patient's charts. Each individual was genotyped using the genome-wide NeuroX array tailored to study neurologic diseases. Genetic data were clustered based on surgical outcome assessed by comparing pre- and post-operative scores of levodopa equivalent daily dose and axial impairment at one and five years post-surgery. Allele frequencies were compared between patients with excellent vs. moderate/poor outcomes grouped using a priori defined cut-offs. We analyzed common variants, burden of rare coding variants, and PD polygenic risk score., Results: NeuroX identified 2,917 polymorphic markers at 113 genes mapped to known PD loci. The gene-burden analyses of 202 rare nonsynonymous variants suggested a nominal association of axial impairment with 14 genes (most consistent with CRHR1, IP6K2, and PRSS3). The strongest association with surgical outcome was detected between a reduction in levodopa equivalent daily dose and common variations tagging two linkage disequilibrium blocks with SH3GL2., Conclusion: Once validated in independent populations, our findings may be implemented to improve patient selection for DBS in PD.
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- 2022
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8. Complex dyskinesias in Parkinson patients on levodopa/carbidopa intestinal gel.
- Author
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Marano M, Naranian T, di Biase L, Di Santo A, Poon YY, Arca R, Cossu G, Marano P, Di Lazzaro V, and Fasano A
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- Aged, Antiparkinson Agents administration & dosage, Carbidopa administration & dosage, Case-Control Studies, Cross-Sectional Studies, Drug Combinations, Dyskinesia, Drug-Induced epidemiology, Female, Gels, Humans, Intestines, Levodopa administration & dosage, Longitudinal Studies, Male, Middle Aged, Retrospective Studies, Antiparkinson Agents adverse effects, Carbidopa adverse effects, Dyskinesia, Drug-Induced etiology, Levodopa adverse effects, Parkinson Disease drug therapy
- Abstract
Background: Levodopa-carbidopa intestinal infusion is an effective treatment for motor fluctuations in Parkinson's disease. However, it has been recently associated with emergent complex/atypical dyskinesias. We sought to characterize patients who developed these dyskinesias after levodopa infusion initiation, and to compare these patients to a control population with conventional motor fluctuations., Methods: 208 Parkinson's disease patients, treated with levodopa intestinal infusion due to motor fluctuations, were screened for onset and/or worsening of dyskinesias after initiation of levodopa infusion, resistant to the routine titration, and presenting with atypical or unexpected patterns. Patients with extensive follow-up data were enrolled for a longitudinal analysis. Cases were compared to a control sample with conventional motor fluctuations in order to investigate predisposing factors, difference in dyskinesia phenotype, management strategies and dropouts., Results: Thirty patients out of 208 (14.4%) reported atypical (i.e. long-lasting) biphasic, biphasic-like (i.e. continuous) or mixed (peak-dose and continuous biphasic) dyskinesias after levodopa infusion. They were compared at baseline and follow-up to a sample of 49 patients with conventional motor fluctuations on levodopa infusion. Both groups had similar demographic and clinical features, except the former having higher prevalence of biphasic dyskinesias while on oral therapy. Biphasic-like dyskinesias in nearly half the number of cases improved with increasing the dopaminergic load, while mixed dyskinesias had the worst outcome and highest dropout rate (58%)., Conclusions: Atypical biphasic, biphasic-like and complex dyskinesias could hinder the course of patients treated with levodopa infusion. This study further informs the selection process of advanced therapies, particularly in dyskinetic patients., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
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- 2019
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9. Levodopa-carbidopa intestinal gel therapy after deep brain stimulation.
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Kumar N, Murgai A, Naranian T, Jog M, and Fasano A
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- Aged, Drug Combinations, Female, Humans, Intestines physiology, Male, Middle Aged, Severity of Illness Index, Treatment Outcome, Antiparkinson Agents therapeutic use, Carbidopa therapeutic use, Deep Brain Stimulation methods, Gels therapeutic use, Intestines drug effects, Levodopa therapeutic use, Parkinson Disease therapy
- Published
- 2018
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10. Enteral feeding in Parkinson's patients receiving levodopa/carbidopa intestinal gel.
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Bove F, Bentivoglio AR, Naranian T, and Fasano A
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- Aged, Drug Combinations, Gels, Humans, Male, Antiparkinson Agents administration & dosage, Carbidopa administration & dosage, Enteral Nutrition methods, Levodopa administration & dosage, Parkinson Disease therapy
- Published
- 2017
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11. SCL20A2 mutation mimicking fluctuating Parkinson's disease.
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Rohani M, Poon YY, Naranian T, and Fasano A
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- Aged, Antiparkinson Agents therapeutic use, Carbidopa therapeutic use, Drug Combinations, Female, Humans, Levodopa therapeutic use, Parkinson Disease diagnostic imaging, Parkinson Disease drug therapy, Parkinson Disease physiopathology, Mutation genetics, Parkinson Disease genetics, Sodium-Phosphate Cotransporter Proteins, Type III genetics
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- 2017
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12. Coenzyme Q10 restores oocyte mitochondrial function and fertility during reproductive aging.
- Author
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Ben-Meir A, Burstein E, Borrego-Alvarez A, Chong J, Wong E, Yavorska T, Naranian T, Chi M, Wang Y, Bentov Y, Alexis J, Meriano J, Sung HK, Gasser DL, Moley KH, Hekimi S, Casper RF, and Jurisicova A
- Subjects
- Animals, Female, Mice, Mice, Transgenic, Mitochondria metabolism, Oocytes cytology, Oocytes metabolism, Ubiquinone pharmacology, Aging drug effects, Fertility drug effects, Mitochondria drug effects, Oocytes drug effects, Reproduction drug effects, Ubiquinone analogs & derivatives
- Abstract
Female reproductive capacity declines dramatically in the fourth decade of life as a result of an age-related decrease in oocyte quality and quantity. The primary causes of reproductive aging and the molecular factors responsible for decreased oocyte quality remain elusive. Here, we show that aging of the female germ line is accompanied by mitochondrial dysfunction associated with decreased oxidative phosphorylation and reduced Adenosine tri-phosphate (ATP) level. Diminished expression of the enzymes responsible for CoQ production, Pdss2 and Coq6, was observed in oocytes of older females in both mouse and human. The age-related decline in oocyte quality and quantity could be reversed by the administration of CoQ10. Oocyte-specific disruption of Pdss2 recapitulated many of the mitochondrial and reproductive phenotypes observed in the old females including reduced ATP production and increased meiotic spindle abnormalities, resulting in infertility. Ovarian reserve in the oocyte-specific Pdss2-deficient animals was diminished, leading to premature ovarian failure which could be prevented by maternal dietary administration of CoQ10. We conclude that impaired mitochondrial performance created by suboptimal CoQ10 availability can drive age-associated oocyte deficits causing infertility., (© 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)
- Published
- 2015
- Full Text
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13. The professional benefits for volunteer research assistants in a pediatric emergency department.
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Steadman PE, Crudden J, Naranian T, Oliveria JP, and Boutis K
- Subjects
- Adult, Allied Health Occupations education, Consumer Behavior statistics & numerical data, Emergency Service, Hospital, Female, Hospitals, Pediatric, Humans, Job Application, Male, Program Evaluation, Prospective Studies, School Admission Criteria statistics & numerical data, Schools, Dental statistics & numerical data, Schools, Medical statistics & numerical data, Schools, Nursing statistics & numerical data, Schools, Pharmacy statistics & numerical data, Surveys and Questionnaires, Young Adult, Correspondence as Topic, Employment statistics & numerical data, Hospital Volunteers statistics & numerical data, Research Personnel statistics & numerical data
- Abstract
Background: Emergency departments (EDs) have utilized university student volunteers to facilitate enrollment of patients into prospective studies; however, the impact of this experience on participant careers is relatively unknown., Objectives: We determined the proportion of successful postgraduate school/research job applications supported by our program reference letter. We also examined participant satisfaction., Methods: This was a prospective cohort study of volunteer research assistants in a tertiary care pediatric ED from September 2011 to July 2013. Students volunteered one 5-h shift per week for at least 6 months. They completed three surveys: 1) Entrance - demographics and goals for entering the ED research assistant program; 2) Exit - program satisfaction, reasons for leaving the program, and future career goals; 3) Follow-up - survey and e-mails were sent to record positions secured since leaving the program., Results: There were a total of 920 applicants over the study period, and 127 volunteers were selected to participate in the program. Response rates for entrance, exit, and follow-up surveys were 100%, 84.9%, and 96.2%, respectively. Of the participants who left and responded, 89/101 (88.9%) obtained school/research positions supported by our program reference letter. Further, 72.6% ranked their satisfaction with the program at least a 7 on a 10-point categorical scale, and 82.9% reported that they "agreed/strongly agreed" that the program helped with their career goals., Conclusions: A volunteer student program is in high demand for university students interested in health sciences/research and potentially has a beneficial career impact for its participants., (Copyright © 2015 Elsevier Inc. All rights reserved.)
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- 2015
- Full Text
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14. The effectiveness of a student volunteer program for research in a pediatric Emergency Department.
- Author
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Steadman PE, Crudden J, Naranian T, Oliveria JP, and Boutis K
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- Cross-Sectional Studies, Data Collection standards, Emergency Service, Hospital, Female, Hospitals, Pediatric, Humans, Informed Consent statistics & numerical data, Male, Program Evaluation, Prospective Studies, Workforce, Biomedical Research statistics & numerical data, Patient Selection, Students, Volunteers
- Abstract
Background: Emergency Department (ED) student-based research assistant programs have been shown to be effective in enrolling patients when the students receive university course credit or pay. However, the impact on research outcomes when university students act as volunteers in this role is relatively unknown., Objectives: The main objective of this study was to determine how often potentially eligible children were accurately identified by volunteer research assistants for enrollment into prospective research in the ED. We also examined the frequency of successful enrollments and the accuracy of data capture., Methods: This was a prospective cross-sectional study of university student volunteer research assistant performance in a tertiary care pediatric ED between March 2011 and July 2013. The participant's primary role was to screen and facilitate enrollment of ED patients into clinical research. For each volunteer, we recorded demographics, number of screenings, enrollments, and data capture accuracy., Results: Over five 6-month sessions, 151 student volunteers participated. Of these, 77.3% were female, 58.8% were undergraduate students, and 61.1% were interested in medical school. Student volunteers accurately screened 11,362/13,067 (87.0%) children, and they accurately identified 4407/4984 (88.4%) potentially eligible children for study enrollment. Of the 3805 eligible for enrollment exclusively by the students, 3228 (84.8%) families/children consented and completed all study procedures. Furthermore, students correctly entered 11,660/12,567 (92.8%) data points., Conclusions: Utilizing university student volunteers to facilitate research enrollment in the ED is effective and allows for the capture of a high percentage of potentially eligible patients into prospective clinical research studies., (Copyright © 2015 Elsevier Inc. All rights reserved.)
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- 2015
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15. In silico prediction of physical protein interactions and characterization of interactome orphans.
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Kotlyar M, Pastrello C, Pivetta F, Lo Sardo A, Cumbaa C, Li H, Naranian T, Niu Y, Ding Z, Vafaee F, Broackes-Carter F, Petschnigg J, Mills GB, Jurisicova A, Stagljar I, Maestro R, and Jurisica I
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- Humans, Proteome, Software, Tumor Suppressor Protein p53 physiology, Computational Biology methods, Computer Simulation, Data Mining methods, Protein Interaction Mapping methods
- Abstract
Protein-protein interactions (PPIs) are useful for understanding signaling cascades, predicting protein function, associating proteins with disease and fathoming drug mechanism of action. Currently, only ∼ 10% of human PPIs may be known, and about one-third of human proteins have no known interactions. We introduce FpClass, a data mining-based method for proteome-wide PPI prediction. At an estimated false discovery rate of 60%, we predicted 250,498 PPIs among 10,531 human proteins; 10,647 PPIs involved 1,089 proteins without known interactions. We experimentally tested 233 high- and medium-confidence predictions and validated 137 interactions, including seven novel putative interactors of the tumor suppressor p53. Compared to previous PPI prediction methods, FpClass achieved better agreement with experimentally detected PPIs. We provide an online database of annotated PPI predictions (http://ophid.utoronto.ca/fpclass/) and the prediction software (http://www.cs.utoronto.ca/~juris/data/fpclass/).
- Published
- 2015
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16. Deficiency of a glycogen synthase-associated protein, Epm2aip1, causes decreased glycogen synthesis and hepatic insulin resistance.
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Turnbull J, Tiberia E, Pereira S, Zhao X, Pencea N, Wheeler AL, Yu WQ, Ivovic A, Naranian T, Israelian N, Draginov A, Piliguian M, Frankland PW, Wang P, Ackerley CA, Giacca A, and Minassian BA
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- Aging genetics, Animals, Dual-Specificity Phosphatases metabolism, Glucose-6-Phosphate metabolism, Glycogen genetics, Glycogen Synthase genetics, Humans, Insulin genetics, Insulin metabolism, Liver enzymology, Liver metabolism, Liver pathology, Mice, Obesity etiology, Obesity genetics, Phosphorylation, Protein Tyrosine Phosphatases, Non-Receptor, Dual-Specificity Phosphatases genetics, Glycogen biosynthesis, Glycogen Synthase metabolism, Insulin Resistance genetics, Obesity pathology
- Abstract
Glycogen synthesis is a major component of the insulin response, and defective glycogen synthesis is a major portion of insulin resistance. Insulin regulates glycogen synthase (GS) through incompletely defined pathways that activate the enzyme through dephosphorylation and, more potently, allosteric activation. We identify Epm2aip1 as a GS-associated protein. We show that the absence of Epm2aip1 in mice impairs allosteric activation of GS by glucose 6-phosphate, decreases hepatic glycogen synthesis, increases liver fat, causes hepatic insulin resistance, and protects against age-related obesity. Our work identifies a novel GS-associated GS activity-modulating component of insulin resistance.
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- 2013
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17. VMA21 deficiency prevents vacuolar ATPase assembly and causes autophagic vacuolar myopathy.
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Ramachandran N, Munteanu I, Wang P, Ruggieri A, Rilstone JJ, Israelian N, Naranian T, Paroutis P, Guo R, Ren ZP, Nishino I, Chabrol B, Pellissier JF, Minetti C, Udd B, Fardeau M, Tailor CS, Mahuran DJ, Kissel JT, Kalimo H, Levy N, Manolson MF, Ackerley CA, and Minassian BA
- Subjects
- Animals, Cells, Cultured, Humans, Hydrogen-Ion Concentration, Leucine metabolism, Lysosomal Storage Diseases pathology, Lysosomes genetics, Lysosomes metabolism, Male, Mice, Muscle, Skeletal metabolism, Muscle, Skeletal pathology, Muscle, Skeletal ultrastructure, Muscular Diseases pathology, Mutation genetics, RNA Interference physiology, RNA, Messenger genetics, Saccharomyces cerevisiae genetics, Saccharomyces cerevisiae metabolism, Saccharomyces cerevisiae Proteins genetics, Saccharomyces cerevisiae Proteins metabolism, Subcellular Fractions metabolism, Subcellular Fractions pathology, Time Factors, Vacuoles metabolism, Adenosine Triphosphatases metabolism, Autophagy genetics, Lysosomal Storage Diseases genetics, Lysosomal Storage Diseases prevention & control, Muscular Diseases genetics, Muscular Diseases prevention & control, Vacuolar Proton-Translocating ATPases deficiency, Vacuolar Proton-Translocating ATPases genetics
- Abstract
X-linked Myopathy with Excessive Autophagy (XMEA) is a childhood onset disease characterized by progressive vacuolation and atrophy of skeletal muscle. We show that XMEA is caused by hypomorphic alleles of the VMA21 gene, that VMA21 is the diverged human ortholog of the yeast Vma21p protein, and that like Vma21p, VMA21 is an essential assembly chaperone of the vacuolar ATPase (V-ATPase), the principal mammalian proton pump complex. Decreased VMA21 raises lysosomal pH which reduces lysosomal degradative ability and blocks autophagy. This reduces cellular free amino acids which leads to downregulation of the mTORC1 pathway, and consequent increased macroautophagy resulting in proliferation of large and ineffective autolysosomes that engulf sections of cytoplasm, merge, and vacuolate the cell. Our results uncover a novel mechanism of disease, namely macroautophagic overcompensation leading to cell vacuolation and tissue atrophy.
- Published
- 2013
- Full Text
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18. NLRP5 mediates mitochondrial function in mouse oocytes and embryos.
- Author
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Fernandes R, Tsuda C, Perumalsamy AL, Naranian T, Chong J, Acton BM, Tong ZB, Nelson LM, and Jurisicova A
- Subjects
- Adenosine Triphosphate metabolism, Animals, Antigens genetics, Cytochromes c metabolism, Egg Proteins genetics, Embryonic Development genetics, Embryonic Development physiology, Female, Gene Expression Regulation, Developmental physiology, Mice, Mice, Knockout, Mitochondria genetics, Ovary embryology, Ovary metabolism, Reactive Oxygen Species metabolism, bcl-2-Associated X Protein biosynthesis, bcl-2-Associated X Protein genetics, Antigens metabolism, Egg Proteins metabolism, Mitochondria metabolism, Oocytes metabolism
- Abstract
Unraveling molecular pathways responsible for regulation of early embryonic development is crucial for our understanding of female infertility. Maternal determinants that control the transition from oocyte to embryo are crucial molecules that govern developmental competence of the newly conceived zygote. We describe a series of defects that are triggered by a disruption of maternal lethal effect gene, Nlrp5. Previous studies have shown that Nlrp5 hypomorph embryos fail to develop beyond the two-cell stage. Despite its importance in preimplantation development, the mechanism by which the embryo arrest occurs remains unclear. We confirmed that Nlrp5 mutant and wild-type females possess comparable ovarian germ pool and follicular recruitment rates. However, ovulated oocytes lacking Nlrp5 have abnormal mitochondrial localization and increased activity in order to sustain physiological ATP content. This results in an accumulation of reactive oxygen species and increased cellular stress causing mitochondrial depletion. Compromised cellular state is also accompanied by increased expression of cell death inducer Bax and depletion of cytochrome c. However, neither genetic deletion (Bax/Nlrp5 double knockout) nor mimetic interference (BH4 domain or Bax inhibitory peptide) were sufficient to alleviate embryo demise caused by depletion of Nlrp5. We therefore conclude that lack of Nlrp5 in oocytes triggers premature activation of the mitochondrial pool, causing mitochondrial damage that cannot be rescued by inactivation of Bax.
- Published
- 2012
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19. VMA21 deficiency causes an autophagic myopathy by compromising V-ATPase activity and lysosomal acidification.
- Author
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Ramachandran N, Munteanu I, Wang P, Aubourg P, Rilstone JJ, Israelian N, Naranian T, Paroutis P, Guo R, Ren ZP, Nishino I, Chabrol B, Pellissier JF, Minetti C, Udd B, Fardeau M, Tailor CS, Mahuran DJ, Kissel JT, Kalimo H, Levy N, Manolson MF, Ackerley CA, and Minassian BA
- Subjects
- Autophagy, Humans, Lysosomes metabolism, Membrane Proteins metabolism, RNA, Messenger metabolism, Saccharomyces cerevisiae Proteins metabolism, Vacuolar Proton-Translocating ATPases genetics, Genes, X-Linked, Muscular Diseases genetics, Vacuolar Proton-Translocating ATPases metabolism
- Abstract
X-linked myopathy with excessive autophagy (XMEA) is a childhood-onset disease characterized by progressive vacuolation and atrophy of skeletal muscle. We show that XMEA is caused by hypomorphic alleles of the VMA21 gene, that VMA21 is the diverged human ortholog of the yeast Vma21p protein, and that like Vma21p it is an essential assembly chaperone of the V-ATPase, the principal mammalian proton pump complex. Decreased VMA21 raises lysosomal pH, which reduces lysosomal degradative ability and blocks autophagy. This reduces cellular free amino acids, which upregulates the mTOR pathway and mTOR-dependent macroautophagy, resulting in proliferation of large and ineffective autolysosomes that engulf sections of cytoplasm, merge together, and vacuolate the cell. Our results uncover macroautophagic overcompensation leading to cell vacuolation and tissue atrophy as a mechanism of disease.
- Published
- 2009
- Full Text
- View/download PDF
20. Lafora progressive myoclonus epilepsy: disease course homogeneity in a genetic isolate.
- Author
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Turnbull J, Kumar S, Ren ZP, Muralitharan S, Naranian T, Ackerley CA, and Minassian BA
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- Adolescent, Adult, Age of Onset, Carrier Proteins metabolism, Consanguinity, DNA Mutational Analysis, Death, Humans, Lafora Disease ethnology, Lafora Disease mortality, Lafora Disease physiopathology, Oman, Skin metabolism, Ubiquitin-Protein Ligases, Carrier Proteins genetics, Lafora Disease genetics, Population Groups genetics
- Abstract
Lafora epilepsy is characterized by starch formation in brain and skin and is diagnosed by skin biopsy or mutation detection. It has variable ages of onset (6-19 years) and death (18-32 years) even with the same mutation, likely due to extramutational factors. The authors identified 14 Lafora epilepsy patients in the genetic isolate of tribal Oman. The authors show that in this homogeneous environment and gene pool, the same mutation, EPM2B-c.468-469delAG, results in highly uniform ages of onset (14 years) and death (21 years). Biopsy, on the other hand, was not homogeneous (positive in 4/5 patients) and is, therefore, less sensitive than mutation testing.
- Published
- 2008
- Full Text
- View/download PDF
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