{"doi":"10.1091/mbc.e09-09-0801","title":"α-Synuclein Delays Endoplasmic Reticulum (ER)-to-Golgi Transport in Mammalian Cells by Antagonizing ER/Golgi SNAREs","abstract":"<jats:p> Toxicity of human α-synuclein when expressed in simple organisms can be suppressed by overexpression of endoplasmic reticulum (ER)-to-Golgi transport machinery, suggesting that inhibition of constitutive secretion represents a fundamental cause of the toxicity. Whether similar inhibition in mammals represents a cause of familial Parkinson's disease has not been established. We tested elements of this hypothesis by expressing human α-synuclein in mammalian kidney and neuroendocrine cells and assessing ER-to-Golgi transport. Overexpression of wild type or the familial disease-associated A53T mutant α-synuclein delayed transport by up to 50%; however, A53T inhibited more potently. The secretory delay occurred at low expression levels and was not accompanied by insoluble α-synuclein aggregates or mistargeting of transport machinery, suggesting a direct action of soluble α-synuclein on trafficking proteins. Co-overexpression of ER/Golgi arginine soluble N-ethylmaleimide-sensitive factor attachment protein receptors (R-SNAREs) specifically rescued transport, indicating that α-synuclein antagonizes SNARE function. Ykt6 reversed α-synuclein inhibition much more effectively than sec22b, suggesting a possible neuroprotective role for the enigmatic high expression of ykt6 in neurons. In in vitro reconstitutions, purified α-synuclein A53T protein specifically inhibited COPII vesicle docking and fusion at a pre-Golgi step. Finally, soluble α-synuclein A53T directly bound ER/Golgi SNAREs and inhibited SNARE complex assembly, providing a potential mechanism for toxic effects in the early secretory pathway. </jats:p>","journal":"Molecular Biology of the Cell","year":2010,"id":16571,"datarank":7.972924009511025,"base_score":5.4116460518550396,"endowment":5.4116460518550396,"self_citation_contribution":0.8117469077782561,"citation_network_contribution":7.161177101732768,"self_endowment_contribution":0.8117469077782561,"citer_contribution":7.161177101732768,"corpus_percentile":null,"corpus_rank":null,"citation_count":223,"citer_count":200,"citers_with_citation_signal":196,"citers_with_endowment":196,"datacite_reuse_total":2,"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":121827,"name":"Jared R. Helm","orcid":null,"position":1,"is_corresponding":false},{"id":121828,"name":"Deborah C. Nycz","orcid":null,"position":2,"is_corresponding":false},{"id":121829,"name":"Marvin Bentley","orcid":null,"position":3,"is_corresponding":false},{"id":121830,"name":"Yingjian Liang","orcid":null,"position":4,"is_corresponding":false},{"id":121831,"name":"Jesse C. Hay","orcid":null,"position":5,"is_corresponding":false},{"id":121826,"name":"Nandhakumar Thayanidhi","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":5.4116460518550396,"endowment":5.4116460518550396,"datacite_reuse_total":2,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"20392839","pmcid":null,"openalex_id":"https://openalex.org/W2140225001","authors":[],"funders":[{"funder_name":"National Institutes of Health","grant_id":"2R01GM059378-06A1","title":"Protein Interactions Controlling ER/Golgi Transport"},{"funder_name":"National Institutes of Health","grant_id":"5R01MH068524-05","title":"Neuronal Ykt6 Protein Interactions and Targeting"},{"funder_name":"NIGMS NIH HHS","grant_id":"GM-59378","title":null},{"funder_name":"NIMH NIH HHS","grant_id":"MH-68524","title":null},{"funder_name":"NCRR NIH HHS","grant_id":"RR-015583","title":null},{"funder_name":"NCRR NIH HHS","grant_id":"P20 RR015583","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"R01 GM059378","title":null},{"funder_name":"NIMH NIH HHS","grant_id":"R01 MH068524","title":null}],"total_grants":8,"fwci":10.7632,"citation_percentile":0.9870388,"influential_citations":8,"citation_trend":[{"year":2012,"count":19},{"year":2013,"count":16},{"year":2014,"count":16},{"year":2015,"count":26},{"year":2016,"count":16},{"year":2017,"count":11},{"year":2018,"count":9},{"year":2019,"count":11},{"year":2020,"count":18},{"year":2021,"count":18},{"year":2022,"count":3},{"year":2023,"count":14},{"year":2024,"count":13},{"year":2025,"count":8},{"year":2026,"count":3}],"oa_status":"green","license":"implied-oa","oa_locations":[{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/2877643","host_type":"repository"},{"url":"https://europepmc.org/articles/pmc2877643?pdf=render","host_type":"GREEN"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/2877643","host_type":"repository"},{"url":"https://doi.org/10.1091/mbc.e09-09-0801","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/20392839","host_type":"repository"},{"url":"http://dx.doi.org/10.1091/mbc.E09-09-0801","host_type":""},{"url":"https://dx.doi.org/10.1091/mbc.e09-09-0801","host_type":""}],"fields_of_study":["Parkinson's Disease Mechanisms and Treatments","Cellular transport and secretion","Alzheimer's disease research and treatments","Biology","Medicine","0301 basic medicine","0303 health sciences","03 medical and health sciences","Animals","COP-Coated Vesicles","Cell Line","Endoplasmic Reticulum","Golgi Apparatus","Humans","Membrane Fusion","Protein Transport","R-SNARE Proteins","Rats","Recombinant Fusion Proteins","alpha-Synuclein"],"mesh_terms":["Animals","Cell Line","Endoplasmic Reticulum","Golgi Apparatus","Humans","Membrane Fusion","Recombinant Fusion Proteins","Protein Transport","COP-Coated Vesicles","R-SNARE Proteins","Rats","alpha-Synuclein"],"keywords":["Endoplasmic reticulum","Golgi apparatus","Biology","Cell biology","COPII","Secretion","Brefeldin A","Secretory pathway","Transport protein","Vesicular transport protein","COPI","Calnexin","ER retention","Vesicle","Mutant","Biochemistry","Calreticulin","Recombinant Fusion Proteins","Articles","Membrane Fusion","Cell Line","Rats","R-SNARE Proteins","Protein Transport","alpha-Synuclein","Animals","Humans","COP-Coated Vesicles"],"sdg_mappings":[],"linked_datasets":[{"doi":"10.6084/m9.figshare.26620276.v1","title":"Additional file 1 of Stable isotope labeling and ultra-high-resolution NanoSIMS imaging reveal alpha-synuclein-induced changes in neuronal metabolism in vivo","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.26620276","title":"Additional file 1 of Stable isotope labeling and ultra-high-resolution NanoSIMS imaging reveal alpha-synuclein-induced changes in neuronal metabolism in vivo","publisher":"figshare","resource_type":"JournalArticle"}],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-06-02T11:43:14.650830Z","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":[]}