{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Lu S"],"funding":["NINDS NIH HHS","U.S. Department of Health & Human Services | National Institutes of Health (NIH)","NIGMS NIH HHS"],"pagination":["1925-1937"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12782899"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["27(11)"],"pubmed_abstract":["In multiple neurodegenerative diseases, the RNA-binding protein TDP-43 forms cytoplasmic aggregates of distinct morphologies, including skein-like, small rounded granular and large spherical inclusions. Here, whereas the N-terminal self-oligomerization domain regulates TDP-43 demixing into cytoplasmic droplets, inhibition of N-terminal self-oligomerization domain-mediated oligomerization is shown to promote the formation of skein-like inclusions. Utilizing proximity labelling-mass spectrometry, cellular stresses are shown to induce TDP-43 association with actin-binding proteins that include filamins and α-actinin. Small interfering RNA-mediated reduction of filamin in Drosophila ameliorates cell loss from cytoplasmic TDP-43, consistent with the filamin-TDP-43 interaction enhancing cytotoxicity. TDP-43's association with actin-binding proteins is mediated by BAG3, a HSP70 family nucleotide exchange factor that regulates the proteostasis of actin-binding proteins. BAG2, another HSP70 nucleotide exchange factor, facilitates the formation of small, rounded TDP-43 inclusions. We demonstrate that both TDP-43 self-oligomerization and its binding partners, including HSP70 and cochaperones BAG2 and BAG3, drive the formation of the different types of TDP-43 inclusion."],"journal":["Nature cell biology"],"pubmed_title":["TDP-43 skein-like inclusions are formed by BAG3- and HSP70-guided co-aggregation with actin-binding proteins."],"pmcid":["PMC12782899"],"funding_grant_id":["P30 NS047101","R01 NS121604","R01 NS027036","R01 NS27036","P41 GM103533"],"pubmed_authors":["Oung S","Han P","Zhang K","Cleveland DW","Arnold-Garcia O","Diedrich JK","Zhang S","Yates Iii JR","Arogundade OA","Lu S","Vazquez-Sanchez S","Ravits J","Ohkubo T"],"additional_accession":[]},"is_claimable":false,"name":"TDP-43 skein-like inclusions are formed by BAG3- and HSP70-guided co-aggregation with actin-binding proteins.","description":"In multiple neurodegenerative diseases, the RNA-binding protein TDP-43 forms cytoplasmic aggregates of distinct morphologies, including skein-like, small rounded granular and large spherical inclusions. Here, whereas the N-terminal self-oligomerization domain regulates TDP-43 demixing into cytoplasmic droplets, inhibition of N-terminal self-oligomerization domain-mediated oligomerization is shown to promote the formation of skein-like inclusions. Utilizing proximity labelling-mass spectrometry, cellular stresses are shown to induce TDP-43 association with actin-binding proteins that include filamins and α-actinin. Small interfering RNA-mediated reduction of filamin in Drosophila ameliorates cell loss from cytoplasmic TDP-43, consistent with the filamin-TDP-43 interaction enhancing cytotoxicity. TDP-43's association with actin-binding proteins is mediated by BAG3, a HSP70 family nucleotide exchange factor that regulates the proteostasis of actin-binding proteins. BAG2, another HSP70 nucleotide exchange factor, facilitates the formation of small, rounded TDP-43 inclusions. We demonstrate that both TDP-43 self-oligomerization and its binding partners, including HSP70 and cochaperones BAG2 and BAG3, drive the formation of the different types of TDP-43 inclusion.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Nov","modification":"2026-06-06T11:44:03.741Z","creation":"2026-05-30T03:07:44.996Z"},"accession":"S-EPMC12782899","cross_references":{"pubmed":["41174004"],"doi":["10.1038/s41556-025-01789-5"]}}