{"doi":"10.1093/braincomms/fcaa010","title":"Analysis of α-synuclein species enriched from cerebral cortex of humans with sporadic dementia with Lewy bodies","abstract":"Since researchers identified α-synuclein as the principal component of Lewy bodies and Lewy neurites, studies have suggested that it plays a causative role in the pathogenesis of dementia with Lewy bodies and other 'synucleinopathies'. While α-synuclein dyshomeostasis likely contributes to the neurodegeneration associated with the synucleinopathies, few direct biochemical analyses of α-synuclein from diseased human brain tissue currently exist. In this study, we analysed sequential protein extracts from a substantial number of patients with neuropathological diagnoses of dementia with Lewy bodies and corresponding controls, detecting a shift of cytosolic and membrane-bound physiological α-synuclein to highly aggregated forms. We then fractionated aqueous extracts (cytosol) from cerebral cortex using non-denaturing methods to search for soluble, disease-associated high molecular weight species potentially associated with toxicity. We applied these fractions and corresponding insoluble fractions containing Lewy-type aggregates to several reporter assays to determine their bioactivity and cytotoxicity. Ultimately, high molecular weight cytosolic fractions enhances phospholipid membrane permeability, while insoluble, Lewy-associated fractions induced morphological changes in the neurites of human stem cell-derived neurons. While the concentrations of soluble, high molecular weight α-synuclein were only slightly elevated in brains of dementia with Lewy bodies patients compared to healthy, age-matched controls, these observations suggest that a small subset of soluble α-synuclein aggregates in the brain may drive early pathogenic effects, while Lewy body-associated α-synuclein can drive neurotoxicity.","journal":"Brain Communications","year":2020,"id":62707,"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":49,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9444,"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":331618,"name":"Suman De","orcid":"0000-0003-1675-0773","position":1,"is_corresponding":false},{"id":331619,"name":"Haiyang Jiang","orcid":"0000-0003-0192-3889","position":2,"is_corresponding":false},{"id":331620,"name":"Matteo Rovere","orcid":"0000-0002-3260-4955","position":3,"is_corresponding":false},{"id":331621,"name":"Ming Jin","orcid":"0000-0002-5550-7533","position":4,"is_corresponding":false},{"id":332990,"name":"Ludovica Zaccagnini","orcid":null,"position":5,"is_corresponding":false},{"id":332991,"name":"Aurelia Hays Watson","orcid":null,"position":6,"is_corresponding":false},{"id":331622,"name":"Laura de Boni","orcid":"0000-0001-7785-482X","position":7,"is_corresponding":false},{"id":308216,"name":"Valentina N. Lagomarsino","orcid":"0000-0003-3195-1899","position":8,"is_corresponding":false},{"id":63306,"name":"Tracy L. Young‐Pearse","orcid":"0000-0001-7846-1542","position":9,"is_corresponding":false},{"id":255563,"name":"Xinyue Liu","orcid":"0000-0002-0934-4155","position":10,"is_corresponding":false},{"id":331623,"name":"Thomas C. Pochapsky","orcid":"0000-0001-8995-1088","position":11,"is_corresponding":false},{"id":19610,"name":"Bradley T. Hyman","orcid":"0000-0002-7959-9401","position":12,"is_corresponding":false},{"id":54753,"name":"Dennis W. Dickson","orcid":"0000-0001-7189-7917","position":13,"is_corresponding":false},{"id":296221,"name":"David Klenerman","orcid":"0000-0001-7116-6954","position":14,"is_corresponding":false},{"id":7839,"name":"Dennis J. Selkoe","orcid":"0000-0001-8846-9767","position":15,"is_corresponding":false},{"id":331624,"name":"Tim Bartels","orcid":"0000-0002-4071-5612","position":16,"is_corresponding":false},{"id":331617,"name":"John Sanderson","orcid":"0000-0002-1168-2540","position":0,"is_corresponding":true}],"reference_count":86,"raw_metadata":null,"created_at":"2026-07-18T21:10:35.996198Z","pmid":"32280944","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":[]}