S-acylation of TDP43 regulates its condensation in amyotrophic lateral sclerosis

  • Mol Cell. 2026 Jun 4;86(11):2191-2206.e8. doi: 10.1016/j.molcel.2026.04.016.
Wentao Xu  1 ,  Huina Li  1 ,  Wei Zhang  1 ,  Ge Bai  2 ,  Chengyong Shen  3 ,  Kejing Zhang  4
Affiliations
  • 1. Department of Neurology of First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310020, China.
  • 2. Department of Neurology of Second Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China; MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University, Hangzhou 310058, China; Nanhu Brain-Computer Interface Institute, Hangzhou 311100, China.
  • 3. Department of Neurology of First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310020, China; MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University, Hangzhou 310058, China; Nanhu Brain-Computer Interface Institute, Hangzhou 311100, China. Electronic address: [email protected].
  • 4. Department of Neurology of First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310020, China; Department of Hepatobiliary and Pancreatic Surgery of the First Affiliated Hospital, Zhejiang Provincial Key Laboratory of Pancreatic Disease, School of Medicine, Zhejiang University, Hangzhou 310020, China. Electronic address: [email protected].
PMID: 42127907 DOI: 10.1016/j.molcel.2026.04.016
Abstract

TDP43 inclusion bodies are widely present in the majority of patients with familial and sporadic amyotrophic lateral sclerosis (ALS). The mechanisms regulating TDP43 solubility remain incompletely understood. Here, we report that TDP43 undergoes S-acylation primarily at the Cys244 residue by the S-acyltransferase zDHHC23. This S-acylation maintains the liquid-like properties of TDP43 by reducing the aberrant interaction with poly(ADP-ribose) polymerase 1 (PARP1) and PARylated proteins, thereby countering the pathological condensation of TDP43. S-acylation-deficient TDP43 inclusions sequester the translational machinery and inhibit cytoplasmic protein translation, ultimately resulting in neurotoxicity. Importantly, TDP43 S-acylation is decreased in the familial ALS-associated TDP43 mutants as well as in SOD1-G93A mice and C9orf72-ALS induced pluripotent stem cell (iPSC)-derived neurons, suggesting the widespread involvement of TDP43 S-acylation in ALS pathogenesis. Our findings reveal an undescribed modification of TDP43 and provide deeper insight into the regulation of TDP43 pathological condensation in ALS.

Keywords
S-acylation; TDP43; aggregation; amyotrophic lateral sclerosis; condensation.
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