{"doi":"10.1101/2025.01.28.635368","title":"Small heat shock protein HSPB8 interacts with a pre-fibrillar TDP43 low complexity domain species to delay fibril formation","abstract":"The loss of cellular proteostasis through aberrant stress granule formation is implicated in neurodegenerative diseases. Stress granules are formed by biomolecular condensation involving protein-protein and protein-RNA interactions. These assemblies are protective, but can rigidify, leading to amyloid-like fibril formation, a hallmark of the disease pathology. Key proteins dictating stress granule formation and disassembly, such as TDP43, contain low-complexity (LC) domains that drive fibril formation. HSPB8, a small heat shock protein, plays a critical role modulating stress granule fluidity, preventing aggregation and promoting degradation of misfolded proteins. We examined the interaction between HSPB8 and the TDP43 LC using thioflavin T (ThT) and fluorescence polarization (FP) aggregation assays, fluorescence microscopy and photobleaching experiments, and crosslinking mass spectrometry (XL-MS). Our results indicate that HSPB8 delays TDP43 LC aggregation through domain-specific interactions with fibril nucleating species, without affecting fibril elongation rates. These findings provide mechanistic insight into how ATP-independent chaperones mediate LC domain aggregation and provide a basis for investigating how the TDP43 LC subverts chaperone activity in neurodegenerative disease.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":555975,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9481,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1455319,"name":"Katherine Corbett","orcid":null,"position":1,"is_corresponding":false},{"id":1455320,"name":"Daniel C. Farb","orcid":null,"position":2,"is_corresponding":false},{"id":1455321,"name":"Kayla M. Osumi","orcid":null,"position":3,"is_corresponding":false},{"id":1455322,"name":"Catelynn C. Shafer","orcid":null,"position":4,"is_corresponding":false},{"id":1455323,"name":"Sophie Criscione","orcid":null,"position":5,"is_corresponding":false},{"id":460591,"name":"Dylan T. Murray","orcid":"0000-0002-2402-810X","position":6,"is_corresponding":false},{"id":824917,"name":"Khaled M. Jami","orcid":"0000-0002-5897-2801","position":0,"is_corresponding":true}],"reference_count":92,"raw_metadata":null,"created_at":"2026-07-19T02:55:03.976486Z","pmid":"39974920","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}