4.8 Article

Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models

Journal

NATURE CHEMICAL BIOLOGY
Volume 10, Issue 8, Pages 677-U119

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/nchembio.1563

Keywords

-

Funding

  1. National Institutes of Neurological Disorders and Stroke [K08 NS072233, 3R01 NS039074, R01 NS083390, R43 NS081844, U24 NS078370]
  2. ALS Association
  3. Robert Packard Center for ALS Research and the William H. Adams Foundation
  4. Target ALS
  5. Roddenberry Stem Cell Program
  6. Taube-Koret Center for Neurodegenerative Disease
  7. Hellman Family Foundation Alzheimer's Disease Research Program
  8. Protein Folding Diseases Initiative at the University of Michigan
  9. California Institute of Regenerative Medicine [TR4-06693, U01 MH1050135]
  10. US National Institutes of Health Extramural Research Facilities Improvement Program Project [C06 RR018928]

Ask authors/readers for more resources

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.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.8
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available