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Nat Chem Biol. 2014 Aug;10(8):677-85. doi: 10.1038/nchembio.1563. Epub 2014 Jun 29.

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

Author information

1
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.
2
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.
3
Gladstone Institute of Neurologic Disease, San Francisco, California, USA.
4
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.
5
1] Gladstone Institute of Neurologic Disease, San Francisco, California, USA. [2] Biomedical Sciences Graduate Program, University of California-San Francisco, San Francisco, California, USA.
6
1] Gladstone Institute of Neurologic Disease, San Francisco, California, USA. [2] Department of Neurobiology and Anatomy, University of Texas Medical School, Houston, Texas, USA.
7
Keck Program in Brain Cell Engineering, Gladstone Institutes, San Francisco, California, USA.
8
Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
9
Institute of Psychiatry, King's College London, London, UK.
10
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.

Abstract

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.

PMID:
24974230
PMCID:
PMC4106236
DOI:
10.1038/nchembio.1563
[Indexed for MEDLINE]
Free PMC Article

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