{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T11:50:33Z","timestamp":1791978633667,"version":"4.4.0"},"reference-count":0,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T00:00:00Z","timestamp":1791936000000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Parkinson\u2019s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are unified by pathological \u03b1-synuclein (\u03b1Syn) aggregation, yet diverge in terms of the cellular distribution of pathology and clinical phenotype. Extracellular vesicles (EVs) have emerged as potential mediators or biomarkers of \u03b1Syn pathology, but whether their molecular constituents in the brain reflect disease-specific processes or conformations remains unknown.<\/jats:p>\n                  <jats:p>Here, we combined EV isolation, electrochemiluminescence, quantitative mass spectrometry and nanoscale single-vesicle imaging by direct stochastic optical reconstruction microscopy (dSTORM) to map the topology, epitope exposure and cellular origin of \u03b1Syn in EVs isolated from post-mortem PD, DLB, MSA, and healthy control (HC) brains and assessed the tractability of these molecular signatures in blood.<\/jats:p>\n                  <jats:p>Proteomics and immunoblotting of EV lysates isolated from human brains confirmed that they were highly purified and derived from neurons and glial cell subtypes. Across diseases, \u03b1Syn association with EVs exhibited distinct patterns: In PD and DLB, both total \u03b1Syn levels normalised to CD81 and the percentage of neuronal (L1CAM+) EVs with aggregated \u03b1Syn as detected by aggregate-preferring antibodies, were increased, whereas in MSA, aggregated \u03b1Syn was detected primarily in neuronal and to a lesser extent glial EV subpopulations without an increase in total EV-associated \u03b1Syn. Further epitope mapping by dSTORM identified a distinct \u03b1Syn conformational arrangement, as detected by antibodies against an epitope spanning \u03b1Syn residues 34\u201345, that was enriched on the surface of L1CAM+ EVs in MSA compared to PD. This N-terminal immunoreactive conformer was tractable in serum and enriched on the surface of L1CAM+ EVs from MSA compared to PD patients or controls.<\/jats:p>\n                  <jats:p>Collectively, our findings suggest that the epitope accessibility and topology of EV-associated \u03b1Syn proteoforms, rather than their abundance alone, discriminate synucleinopathy subtypes, offering a framework for a blood-based conformational stratification of these disorders.<\/jats:p>","DOI":"10.1093\/brain\/awag356","type":"journal-article","created":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T11:41:06Z","timestamp":1791891666000},"source":"Crossref","is-referenced-by-count":0,"title":["Extracellular vesicle \u03b1-synuclein topology reveals disease-associated conformers in brain and blood"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9189-7962","authenticated-orcid":false,"given":"Suman","family":"Dutta","sequence":"first","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences, University of Oxford , Oxford, OX3 9DU ,","place":["UK"]},{"name":"Kavli Institute for Nanoscience Discovery, University of Oxford , Oxford, OX1 3QU ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amin","family":"Atashgaran","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences, University of Oxford , Oxford, OX3 9DU ,","place":["UK"]},{"name":"Kavli Institute for Nanoscience Discovery, University of Oxford , Oxford, OX1 3QU ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anis","family":"Sahoo","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences, University of Oxford , Oxford, OX3 9DU ,","place":["UK"]},{"name":"Kavli Institute for Nanoscience Discovery, University of Oxford , Oxford, OX1 3QU ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stelios","family":"Chatzimichail","sequence":"additional","affiliation":[{"name":"Kavli Institute for Nanoscience Discovery, University of Oxford , Oxford, OX1 3QU ,","place":["UK"]},{"name":"Department of Physics, University of Oxford , Oxford, OX1 3PU ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Achillefs N","family":"Kapanidis","sequence":"additional","affiliation":[{"name":"Kavli Institute for Nanoscience Discovery, University of Oxford , Oxford, OX1 3QU ,","place":["UK"]},{"name":"Department of Physics, University of Oxford , Oxford, OX1 3PU ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9252-5933","authenticated-orcid":false,"given":"George K","family":"Tofaris","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences, University of Oxford , Oxford, OX3 9DU ,","place":["UK"]},{"name":"Kavli Institute for Nanoscience Discovery, University of Oxford , Oxford, OX1 3QU ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,10,14]]},"container-title":["Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awag356\/71943084\/awag356.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awag356\/71943084\/awag356.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T11:14:53Z","timestamp":1791976493000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/brain\/advance-article\/doi\/10.1093\/brain\/awag356\/8916294"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,14]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1093\/brain\/awag356","relation":{},"ISSN":["0006-8950","1460-2156"],"issn-type":[{"value":"0006-8950","type":"print"},{"value":"1460-2156","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,14]]},"article-number":"awag356"}}