biostudies-literatureBarmada SJNIMH NIH HHSNINDS NIH HHSMotor Neurone Disease Association677-85https://www.ebi.ac.uk/biostudies/studies/S-EPMC4106236biostudies-literatureUnknown10(8)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 inNature chemical biologyAutophagy induction enhances TDP43 turnover and survival in neuronal ALS models.PMC4106236U24 NS078370R43 NS081844CHANDRAN/MAR10/982-797K08 NS072233R01 NS083390U01 MH10501353R01 NS039074U01 MH105035R01 NS039074Bilican BPeisach DShaw CTsvetkov ABarmada SJAndo DMSerio ALi XFinkbeiner SArjun APleiss MDaub AChandran SfalseAutophagy induction enhances TDP43 turnover and survival in neuronal ALS models.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 in2014-01-01T00:00:00Z2014 Aug2025-04-19T04:16:11.103Z2019-03-27T01:32:31ZS-EPMC41062362497423010.1038/nchembio.1563