{"doi":"10.1038/s41467-018-03509-0","title":"A common mechanism of proteasome impairment by neurodegenerative disease-associated oligomers","abstract":"<jats:title>Abstract</jats:title><jats:p>Protein accumulation and aggregation with a concomitant loss of proteostasis often contribute to neurodegenerative diseases, and the ubiquitin–proteasome system plays a major role in protein degradation and proteostasis. Here, we show that three different proteins from Alzheimer’s, Parkinson’s, and Huntington’s disease that misfold and oligomerize into a shared three-dimensional structure potently impair the proteasome. This study indicates that the shared conformation allows these oligomers to bind and inhibit the proteasome with low nanomolar affinity, impairing ubiquitin-dependent and ubiquitin-independent proteasome function in brain lysates. Detailed mechanistic analysis demonstrates that these oligomers inhibit the 20S proteasome through allosteric impairment of the substrate gate in the 20S core particle, preventing the 19S regulatory particle from injecting substrates into the degradation chamber. These results provide a novel molecular model for oligomer-driven impairment of proteasome function that is relevant to a variety of neurodegenerative diseases, irrespective of the specific misfolded protein that is involved.</jats:p>","journal":"Nature Communications","year":2018,"id":22742,"datarank":7.217097815624471,"base_score":5.8998973535824915,"endowment":5.8998973535824915,"self_citation_contribution":0.8849846030373738,"citation_network_contribution":6.332113212587097,"self_endowment_contribution":0.8849846030373738,"citer_contribution":6.332113212587097,"corpus_percentile":null,"corpus_rank":null,"citation_count":364,"citer_count":200,"citers_with_citation_signal":200,"citers_with_endowment":200,"datacite_reuse_total":4,"is_dataset":false,"is_dataset_confidence":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":141991,"name":"Raymond T. Anderson","orcid":null,"position":1,"is_corresponding":false},{"id":141992,"name":"David M. Smith","orcid":"0000-0002-1502-676X","position":2,"is_corresponding":false},{"id":141990,"name":"Tiffany A. Thibaudeau","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":5.8998973535824915,"endowment":5.8998973535824915,"datacite_reuse_total":4,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"29545515","pmcid":"PMC5854577","openalex_id":"https://openalex.org/W2789933553","authors":[],"funders":[{"funder_name":"NIGMS NIH HHS","grant_id":"R01 GM107129","title":null},{"funder_name":"National Institutes of Health","grant_id":"5R01GM107129-04","title":"Mechanisms regulating proteasomal substrate degradation"}],"total_grants":2,"fwci":12.5222,"citation_percentile":0.99252763,"influential_citations":5,"citation_trend":[{"year":2018,"count":8},{"year":2019,"count":31},{"year":2020,"count":50},{"year":2021,"count":46},{"year":2022,"count":47},{"year":2023,"count":60},{"year":2024,"count":51},{"year":2025,"count":52},{"year":2026,"count":18}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.nature.com/articles/s41467-018-03509-0.pdf","host_type":"journal"},{"url":"https://www.nature.com/articles/s41467-018-03509-0.pdf","host_type":"GOLD"},{"url":"https://www.nature.com/articles/s41467-018-03509-0.pdf","host_type":"publisher"},{"url":"https://www.nature.com/articles/s41467-018-03509-0","host_type":"publisher"},{"url":"https://doi.org/10.1038/s41467-018-03509-0","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/29545515","host_type":"repository"},{"url":"https://researchrepository.wvu.edu/faculty_publications/1732","host_type":"repository"},{"url":"https://doaj.org/article/66adbe031f284b1c992c3c4f8315ec3d","host_type":"repository"},{"url":"https://doaj.org/article/dbd047c274eb4a5da7f8fbf90d88ffc5","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/5854577","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC5854577","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC5854577?pdf=render","host_type":"Europe_PMC"},{"url":"https://doi.org/10.1096/fasebj.31.1_supplement.763.8","host_type":""},{"url":"http://dx.doi.org/10.1038/s41467-018-03509-0","host_type":""},{"url":"https://dx.doi.org/10.1038/s41467-018-03509-0","host_type":""}],"fields_of_study":["Ubiquitin and proteasome pathways","Endoplasmic Reticulum Stress and Disease","Autophagy in Disease and Therapy","Chemistry","Medicine","Biology","0301 basic medicine","0303 health sciences","03 medical and health sciences","Animals","Cattle","Escherichia coli","Humans","Mice","Neurodegenerative Diseases","Proteasome Endopeptidase Complex","Protein Conformation","Protein Folding"],"mesh_terms":["Animals","Cattle","Escherichia coli","Humans","Protein Conformation","Protein Folding","Neurodegenerative Diseases","Proteasome Endopeptidase Complex","Mice"],"keywords":["Proteostasis","Proteasome","Ubiquitin","Lactacystin","Cell biology","Neurodegeneration","Allosteric regulation","Protein folding","Chemistry","Oligomer","Protein aggregation","Biochemistry","Biology","Proteasome inhibitor","Disease","Medicine","Enzyme","Proteasome Endopeptidase Complex","Protein Conformation","Science","Q","Neurodegenerative Diseases","Article","Mice","Escherichia coli","Animals","Humans","Cattle"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. Good health"},{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[{"doi":"10.6084/m9.figshare.26583705.v1","title":"Additional file 1 of Proteomic signature associated with chronic kidney disease (CKD) progression identified by data-independent acquisition mass spectrometry","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.26583705","title":"Additional file 1 of Proteomic signature associated with chronic kidney disease (CKD) progression identified by data-independent acquisition mass spectrometry","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.26583708.v1","title":"Additional file 2 of Proteomic signature associated with chronic kidney disease (CKD) progression identified by data-independent acquisition mass spectrometry","publisher":"figshare","resource_type":"Dataset"},{"doi":"10.6084/m9.figshare.26583708","title":"Additional file 2 of Proteomic signature associated with chronic kidney disease (CKD) progression identified by data-independent acquisition mass spectrometry","publisher":"figshare","resource_type":"Dataset"}],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-06-07T15:55:36.780687Z","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,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}