Proteasomal-dependent CHK1 degradation leads to DNA damage accumulation in ALS cellular model systems
Stefania Modafferi, Valentina Silenzi, Anna Garbelli, Gloria Lazoi, Eveljn Scarian, Sara D’Uva, Tiziana Santini, A. Riccardi, Mauro Cozzolino, Orietta Pansarasa, Nadia D’Ambrosi, Simone Sabbioneda, Mariangela Morlando, Sofia Francia
Cell Death and Disease, Vol. 17, Issue 1 (2026)
10.1038/s41419-026-08603-6
PMID: 42086533
Abstract
Amyotrophic lateral sclerosis (ALS) is characterised by the aggregation of TDP-43 and mutant FUS in the cytoplasm of affected motor neurons. Accumulation of DNA damage is emerging as a novel correlative trait of ALS. We recently showed that formation of TDP-43 and FUS cytoplasmic inclusions (CIs) lead to DNA damage accumulation through dysregulation of the DNA damage response (DDR). However, the multiple molecular mechanisms contributing to DNA damage accumulation in affected motor neurons in ALS have not been fully elucidated. In recent years, chemical inhibition of the serine/threonine kinase CHK1 was shown to lead to accumulation of DNA breaks as well as increased apoptosis, in differentiated cortical neurons. Notably, CHK1 has been involved in DNA double-strand break repair in non-dividing cells, by acting through the histone chaperone ASF1A. In this article, we show that cells bearing FUS and TDP-43 CIs show downregulation of the protein levels of CHK1 and ASF1A. We observe CHK1 protein downregulation in neuronal cell lines, as well as in patient-derived motor neurons progenitors and in the spinal cord of a FUS-ALS mouse model. Restoration of the nuclear levels of CHK1 and ASF1A via transient overexpression, is sufficient to reduce DNA damage signal accumulation and rescues DDR defects. Importantly, we show that the ubiquitin-proteasome pathway is responsible for CHK1 degradation in cells bearing FUS CI, since its inhibition restores CHK1 and ASF1A protein levels. Our study demonstrates that proteasomal-dependent CHK1 and ASF1A downregulation contributes to accumulation of DNA damage in cells affected by ALS-linked protein aggregates.
Topics
Field: Medicine · Subfield: Neurology
Keywords
DNA damage,Downregulation and upregulation,DNA repair,Histone,CHEK1,Nuclear protein,Cytoplasm,Protein kinase A,DNA
MeSH Terms
UN Sustainable Development Goals
- Life in Land (0.43)
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