{"doi":"10.1101/2020.04.15.043935","title":"Tuning Hsp104 specificity to selectively detoxify α-synuclein","abstract":"Summary Hsp104 is an AAA+ protein disaggregase that solubilizes and reactivates proteins trapped in aggregated states. We have engineered potentiated Hsp104 variants to mitigate toxic misfolding of α-synuclein, TDP-43, and FUS implicated in fatal neurodegenerative disorders. Though potent disaggregases, these enhanced Hsp104 variants lack substrate specificity, and can have unfavorable off-target effects. Here, to lessen off-target effects, we engineer substrate-specific Hsp104 variants. By altering Hsp104 pore loops that engage substrate, we disambiguate Hsp104 variants that selectively suppress α-synuclein toxicity but not TDP-43 or FUS toxicity. Remarkably, α-synuclein-specific Hsp104 variants emerge that mitigate α-synuclein toxicity via distinct ATPase-dependent mechanisms, involving α-synuclein disaggregation or detoxification of α-synuclein conformers without disaggregation. Importantly, both types of α-synuclein-specific Hsp104 variant reduce dopaminergic neurodegeneration in a C. elegans model of Parkinson’s disease more effectively than non-specific variants. We suggest that increasing the substrate specificity of enhanced disaggregases could be applied broadly to tailor therapeutics for neurodegenerative disease.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":122711,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9465,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":492657,"name":"Hanna Kim","orcid":"0000-0003-1362-371X","position":1,"is_corresponding":false},{"id":444031,"name":"Meredith E. Jackrel","orcid":"0000-0003-4406-9504","position":2,"is_corresponding":false},{"id":480604,"name":"JiaBei Lin","orcid":"0000-0001-8863-1859","position":3,"is_corresponding":false},{"id":355086,"name":"Jamie E. DeNizio","orcid":null,"position":4,"is_corresponding":false},{"id":492658,"name":"Xiaohui Yan","orcid":"0000-0001-7295-8902","position":5,"is_corresponding":false},{"id":492659,"name":"Edward Chuang","orcid":"0000-0002-6380-7317","position":6,"is_corresponding":false},{"id":565308,"name":"Amber Tariq","orcid":null,"position":7,"is_corresponding":false},{"id":302139,"name":"Ryan R. Cupo","orcid":"0000-0001-7639-1923","position":8,"is_corresponding":false},{"id":493306,"name":"Laura M. Castellano","orcid":null,"position":9,"is_corresponding":false},{"id":257435,"name":"Kim A. Caldwell","orcid":"0000-0003-1580-6122","position":10,"is_corresponding":false},{"id":257437,"name":"Guy A. Caldwell","orcid":"0000-0002-8283-9090","position":11,"is_corresponding":false},{"id":268287,"name":"James Shorter","orcid":"0000-0001-5269-8533","position":12,"is_corresponding":false},{"id":343962,"name":"Korrie L. Mack","orcid":"0000-0002-7678-146X","position":0,"is_corresponding":true}],"reference_count":94,"raw_metadata":null,"created_at":"2026-07-18T23:14:55.385653Z","pmid":null,"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":[]}