دورية أكاديمية
أعرض في EDS

Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models.

التفاصيل البيبلوغرافية
العنوان: Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models.
المؤلفون: Barmada SJ; 1] Gladstone Institute of Neurologic Disease, San Francisco, California, USA. [2] Department of Neurology, University of California-San Francisco Medical Center, San Francisco, California, USA. [3] Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA., Serio A; 1] Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, Scotland, UK. [2] Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, Scotland, UK. [3] Departments of Materials and Bioengineering, and Institute for Biomedical Engineering, Imperial College, London, UK., Arjun A; Gladstone Institute of Neurologic Disease, San Francisco, California, USA., Bilican B; 1] Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, Scotland, UK. [2] Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, Scotland, UK., Daub A; Gladstone Institute of Neurologic Disease, San Francisco, California, USA., Ando DM; 1] Gladstone Institute of Neurologic Disease, San Francisco, California, USA. [2] Biomedical Sciences Graduate Program, University of California-San Francisco, San Francisco, California, USA., Tsvetkov A; 1] Gladstone Institute of Neurologic Disease, San Francisco, California, USA. [2] Department of Neurobiology and Anatomy, University of Texas Medical School, Houston, Texas, USA., Pleiss M; Keck Program in Brain Cell Engineering, Gladstone Institutes, San Francisco, California, USA., Li X; Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA., Peisach D; Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA., Shaw C; Institute of Psychiatry, King's College London, London, UK., Chandran S; 1] Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, Scotland, UK. [2] Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, Scotland, UK., Finkbeiner S; 1] Gladstone Institute of Neurologic Disease, San Francisco, California, USA. [2] Department of Neurology, University of California-San Francisco Medical Center, San Francisco, California, USA. [3] Biomedical Sciences Graduate Program, University of California-San Francisco, San Francisco, California, USA. [4] Keck Program in Brain Cell Engineering, Gladstone Institutes, San Francisco, California, USA. [5] Department of Physiology, University of California-San Francisco, San Francisco, California, USA. [6] Taube-Koret Center for Neurodegenerative Disease Research, San Francisco, California, USA. [7] Hellman Family Foundation Alzheimer's Disease Research Program, San Francisco, California, USA. [8] Roddenberry Stem Cell Program, San Francisco, California, USA.
المصدر: Nature chemical biology [Nat Chem Biol] 2014 Aug; Vol. 10 (8), pp. 677-85. Date of Electronic Publication: 2014 Jun 29.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: United States NLM ID: 101231976 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1552-4469 (Electronic) Linking ISSN: 15524450 NLM ISO Abbreviation: Nat Chem Biol Subsets: MEDLINE
أسماء مطبوعة: Original Publication: New York, NY : Nature Pub. Group, [2005]-
مواضيع طبية MeSH: Autophagy*/drug effects, Amyotrophic Lateral Sclerosis/*metabolism , DNA-Binding Proteins/*metabolism , Neurons/*metabolism, Amino Acid Sequence ; Amyotrophic Lateral Sclerosis/pathology ; Animals ; Astrocytes/metabolism ; Cell Survival ; Cells, Cultured ; DNA-Binding Proteins/genetics ; Fluphenazine/pharmacology ; Half-Life ; Humans ; Induced Pluripotent Stem Cells/physiology ; Methotrimeprazine/pharmacology ; Mice ; Microtubule-Associated Proteins/genetics ; Microtubule-Associated Proteins/metabolism ; Molecular Sequence Data ; Mutation ; Rats ; Reproducibility of Results ; Single-Cell Analysis/methods ; Small Molecule Libraries/pharmacology ; Stem Cells/metabolism
مستخلص: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have distinct clinical features but a common pathology--cytoplasmic inclusions rich in transactive response element DNA-binding protein of 43 kDa (TDP43). Rare TDP43 mutations cause ALS or FTD, but abnormal TDP43 levels and localization may cause disease even if TDP43 lacks a mutation. Here we show that individual neurons vary in their ability to clear TDP43 and are exquisitely sensitive to TDP43 levels. To measure TDP43 clearance, we developed and validated a single-cell optical method that overcomes the confounding effects of aggregation and toxicity and discovered that pathogenic mutations shorten TDP43 half-life. New compounds that stimulate autophagy improved TDP43 clearance and localization and enhanced survival in primary murine neurons and in human stem cell-derived neurons and astrocytes harboring mutant TDP43. These findings indicate that the levels and localization of TDP43 critically determine neurotoxicity and show that autophagy induction mitigates neurodegeneration by acting directly on TDP43 clearance.
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معلومات مُعتمدة: 3R01 NS039074 United States NS NINDS NIH HHS; R01 NS039074 United States NS NINDS NIH HHS; U24 NS078370 United States NS NINDS NIH HHS; U01 MH105035 United States MH NIMH NIH HHS; R43 NS081844 United States NS NINDS NIH HHS; C06 RR018928 United States RR NCRR NIH HHS; R01 NS083390 United States NS NINDS NIH HHS; U01 MH1050135 United States MH NIMH NIH HHS; K08 NS072233 United States NS NINDS NIH HHS; CHANDRAN/MAR10/982-797 United Kingdom MNDA_ Motor Neurone Disease Association
سلسلة جزيئية: PubChem-Substance 183814147; 183814148; 183814149
المشرفين على المادة: 0 (DNA-Binding Proteins)
0 (LC3 protein, rat)
0 (Microtubule-Associated Proteins)
0 (Small Molecule Libraries)
9G0LAW7ATQ (Methotrimeprazine)
S79426A41Z (Fluphenazine)
تواريخ الأحداث: Date Created: 20140630 Date Completed: 20141006 Latest Revision: 20240610
رمز التحديث: 20240610
مُعرف محوري في PubMed: PMC4106236
DOI: 10.1038/nchembio.1563
PMID: 24974230
قاعدة البيانات: MEDLINE
الوصف
تدمد:1552-4469
DOI:10.1038/nchembio.1563