Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Astrocytes / metabolism
  • Autophagy* / drug effects
  • Cell Survival
  • Cells, Cultured
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Fluphenazine / pharmacology
  • Half-Life
  • Humans
  • Induced Pluripotent Stem Cells / physiology
  • Methotrimeprazine / pharmacology
  • Mice
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Molecular Sequence Data
  • Mutation
  • Neurons / metabolism*
  • Rats
  • Reproducibility of Results
  • Single-Cell Analysis / methods
  • Small Molecule Libraries / pharmacology
  • Stem Cells / metabolism


  • DNA-Binding Proteins
  • LC3 protein, rat
  • Microtubule-Associated Proteins
  • Small Molecule Libraries
  • Methotrimeprazine
  • Fluphenazine

Associated data

  • PubChem-Substance/183814147
  • PubChem-Substance/183814148
  • PubChem-Substance/183814149