{"doi":"10.17615/7p2v-4235","title":"Familial Parkinson's Disease-associated L166P Mutation Disrupts DJ-1 Protein Folding and Function","abstract":"Mutations in DJ-1, a protein of unknown function, were recently identified as the cause for an autosomal recessive, early onset form of familial Parkinson's disease. Here we report that DJ-1 is a dimeric protein that exhibits protease activity but no chaperone activity. The protease activity was abolished by mutation of Cys-106 to Ala, suggesting that DJ-1 functions as a cysteine protease. Our studies revealed that the Parkinson's disease-linked L166P mutation impaired the intrinsic folding propensity of DJ-1 protein, resulting in a spontaneously unfolded structure that was incapable of forming a homodimer with itself or a heterodimer with wild-type DJ-1. Correlating with the disruption of DJ-1 structure, the L166P mutation abolished the catalytic function of DJ-1. Furthermore, as a result of protein misfolding, the L166P mutant DJ-1 was selectively polyubiquitinated and rapidly degraded by the proteasome. Together these findings provide insights into the molecular mechanism by which loss-of-function mutations in DJ-1 lead to Parkinson's disease.","journal":"UNC Libraries","year":2021,"id":230187,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9537,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":836429,"name":"Howard D. Rees","orcid":null,"position":1,"is_corresponding":false},{"id":519449,"name":"Hengming Ke","orcid":"0000-0001-8864-7279","position":2,"is_corresponding":false},{"id":836017,"name":"Keith Brown","orcid":"0000-0001-6922-6014","position":3,"is_corresponding":false},{"id":744158,"name":"Lih Shen Chin","orcid":null,"position":4,"is_corresponding":false},{"id":146881,"name":"Keith D. Wilkinson","orcid":null,"position":5,"is_corresponding":false},{"id":603038,"name":"Qing Huai","orcid":null,"position":6,"is_corresponding":false},{"id":166314,"name":"James A. Olzmann","orcid":"0000-0001-7751-8316","position":7,"is_corresponding":false},{"id":68010,"name":"Allan I. Levey","orcid":"0000-0002-3153-502X","position":8,"is_corresponding":false},{"id":272045,"name":"Lian Li","orcid":"0000-0003-4700-1134","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:55:05.844766Z","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":[]}