Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models
| Autor: | Daniel Peisach, Steven Finkbeiner, Andrea Serio, D. Michael Ando, Andrey S. Tsvetkov, Xingli Li, Siddharthan Chandran, Bilada Bilican, Michael A. Pleiss, Aaron C. Daub, Arpana Arjun, Christopher Shaw, Sami J. Barmada |
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| Rok vydání: | 2014 |
| Předmět: |
Biochemistry & Molecular Biology
Cell Survival Mutant Induced Pluripotent Stem Cells Molecular Sequence Data Biology medicine.disease_cause Article Small Molecule Libraries Mice Medicinal and Biomolecular Chemistry medicine Autophagy Fluphenazine Methotrimeprazine Animals Humans Amino Acid Sequence Amyotrophic lateral sclerosis Molecular Biology Cells Cultured Genetics Neurons Mutation Stem Cells Neurodegeneration Amyotrophic Lateral Sclerosis Neurotoxicity Reproducibility of Results Cell Biology medicine.disease 3. Good health Cell biology Rats DNA-Binding Proteins Astrocytes Biochemistry and Cell Biology Stem cell Single-Cell Analysis Microtubule-Associated Proteins Frontotemporal dementia Half-Life |
| Zdroj: | Nature Chemical Biology, vol 10, iss 8 Nature chemical biology Barmada, SJ; Serio, A; Arjun, A; Bilican, B; Daub, A; Ando, DM; et al.(2014). Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models. Nature Chemical Biology, 10(8), 677-685. doi: 10.1038/nchembio.1563. UC San Francisco: Retrieved from: http://www.escholarship.org/uc/item/6z83h67w |
| DOI: | 10.1038/nchembio.1563. |
| Popis: | 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. © 2014 Nature America, Inc. All rights reserved. |
| Databáze: | OpenAIRE |
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