PXD061643

PXD061643 is an original dataset announced via ProteomeXchange.

Title	S-acylation of TDP43 regulates its condensation in amyotrophic lateral sclerosis
Description	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.
HostingRepository	PRIDE
AnnounceDate	2026-05-17
AnnouncementXML	Submission_2026-05-16_16:46:39.287.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Wentao Xu
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2025-03-10 04:08:02	ID requested
⏵ 1	2026-05-16 16:46:40	announced

Xu W, Li H, Zhang W, Bai G, Shen C, Zhang K, S-acylation of TDP43 regulates its condensation in amyotrophic lateral sclerosis. Mol Cell, 86(11):2191-2206.e8(2026) [pubmed]

10.1016/j.molcel.2026.04.016;

submitter keyword: None

Chengyong Shen
contact affiliation	Institute of Translational Medicine, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, School of Medicine, Zhejiang University, Zhejiang, China.
contact email	cshen@zju.edu.cn
lab head
Wentao Xu
contact affiliation	Zhejiang University School of Medicine
contact email	wentaoxu@zju.edu.cn
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/05/PXD061643

PRIDE project URI

• PRIDE
  1. PXD061643
     1. Label: PRIDE project
     2. Name: S-acylation of TDP43 regulates its condensation in amyotrophic lateral sclerosis