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.
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Acknowledgements
We would like to thank B. Miller, B. Seeley, C. Lomen-Hoerth and the members of the Finkbeiner lab for their generous support and advice. H. Zahed and J. Margulis deserve special acknowledgment for their assistance. We thank G. Howard for editorial assistance and K. Nelson for administrative assistance. We also thank G. Yu and J. Herz (University of Texas, Southwestern) for anti-TDP43 antibodies. This work was supported by National Institutes of Neurological Disorders and Stroke grants K08 NS072233 (to S.J.B.), 3R01 NS039074, R01 NS083390, R43 NS081844 and U24 NS078370 (to S.F.); the ALS Association (S.F.); the Robert Packard Center for ALS Research and the William H. Adams Foundation (S.F.); and Target ALS (S.F.). Additional support was provided by the Roddenberry Stem Cell Program (to S.F.), the Taube-Koret Center for Neurodegenerative Disease (S.F.), the Hellman Family Foundation Alzheimer's Disease Research Program (S.F.), the Protein Folding Diseases Initiative at the University of Michigan (S.J.B.) and the California Institute of Regenerative Medicine TR4-06693 (S.F.) and U01 MH1050135 (S.F.). The animal care facility was partly supported by an US National Institutes of Health Extramural Research Facilities Improvement Program Project (C06 RR018928).
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S.J.B., A.S., A.A., A.T., S.C. and S.F. designed the study. S.J.B., A.A., X.L. and A.S. cultured cells, performed microscopy and conducted survival analyses. A.T., B.B., C.S. and S.C. provided compounds and iPSCs. M.P. performed in silico drug screening. D.P., D.M.A. and A.D. wrote original scripts for AFM. S.J.B. and A.A. analyzed data, constructed vectors, performed MPC and OPL and transfected neurons. S.B. and S.F. wrote and edited the manuscript.
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Barmada, S., Serio, A., Arjun, A. et al. Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models. Nat Chem Biol 10, 677–685 (2014). https://doi.org/10.1038/nchembio.1563
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DOI: https://doi.org/10.1038/nchembio.1563
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