Autophagy Induction Enhances TDP43 Turnover and Survival in Neuronal ALS Models

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2014 Jun 30

PMID 24974230

Citations 247

Authors

Sami J Barmada

Andrea Serio

Arpana Arjun

Bilada Bilican

Aaron Daub

D Michael Ando

Andrey Tsvetkov

Michael Pleiss

Xingli Li

Daniel Peisach

Christopher Shaw

Siddharthan Chandran

Steven Finkbeiner

Affiliations

Soon will be listed here.

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.

Citing Articles

Epigenetic regulation of TDP-43: potential implications for amyotrophic lateral sclerosis.

Mengistu D, Terribili M, Pellacani C, Ciapponi L, Marzullo M Front Mol Med. 2025; 5:1530719.

PMID: 40017539 PMC: 11865237. DOI: 10.3389/fmmed.2025.1530719.

Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS.

Bekier M, Bekier 2nd M, Pinarbasi E, Mesojedec J, Ghaffari L, de Majo M bioRxiv. 2025; .

PMID: 39975323 PMC: 11838369. DOI: 10.1101/2025.01.27.635090.

TDP43 autoregulation gives rise to dominant negative isoforms that are tightly controlled by transcriptional and post-translational mechanisms.

Dykstra M, Weskamp K, Gomez N, Waksmacki J, Tank E, Glineburg M Cell Rep. 2025; 44(1):115113.

PMID: 39792557 PMC: 11848802. DOI: 10.1016/j.celrep.2024.115113.

Targeting common disease pathomechanisms to treat amyotrophic lateral sclerosis.

Faller K, Chaytow H, Gillingwater T Nat Rev Neurol. 2025; 21(2):86-102.

PMID: 39743546 DOI: 10.1038/s41582-024-01049-4.

Autophagy receptor-inspired chimeras: a novel approach to facilitate the removal of protein aggregates and organelle by autophagy degradation.

Wang L, Liu H, Li L J Zhejiang Univ Sci B. 2025; 25(12):1115-1119.

PMID: 39743298 PMC: 11693386. DOI: 10.1631/jzus.B2300853.

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