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However, structural differences between human brain-derived and SAA \u03b1Syn \ufb01brils have been recently highlighted. Here, we characterize the biophysical properties of the human brain-derived \u03b1Syn \ufb01brils from the brains of patients with Parkinson\u2019s disease with and without dementia (PD, PDD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and compare them to the \u2018model\u2019 SAA \ufb01brils. We report that the brain-derived \u03b1Syn \ufb01brils show distinct biochemical pro\ufb01les, which were not replicated in the corresponding SAA \ufb01brils. Furthermore, the brain-derived \u03b1Syn \ufb01brils from all synucleinopathies displayed a mixture of \u2018straight\u2019 and \u2018twisted\u2019 microscopic structures. However, the PD, PDD, and DLB SAA \ufb01brils had a \u2019straight\u2019 structure, whereas MSA SAA \ufb01brils showed a \u2018twisted\u2019 structure. Finally, the brain-derived \u03b1Syn \ufb01brils from all four synucleinopathies were phosphorylated (S129). Interestingly, phosphorylated \u03b1Syn were carried over to the PDD and DLB SAA fibrils. Our \ufb01ndings demonstrate the limitation of the SAA \ufb01brils modeling the brain-derived \u03b1Syn \ufb01brils and pay attention to the necessity of deepening the understanding of the SAA fibrillation methodology.<\/jats:p>","DOI":"10.7554\/elife.92775","type":"journal-article","created":{"date-parts":[[2024,3,21]],"date-time":"2024-03-21T10:26:00Z","timestamp":1711016760000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.92775","source":"Crossref","is-referenced-by-count":8,"title":["Brain-derived and in vitro-seeded alpha-synuclein fibrils exhibit distinct biophysical profiles"],"prefix":"10.7554","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2801-6202","authenticated-orcid":true,"given":"Selene Seoyun","family":"Lee","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/052gg0110","id-type":"ROR","asserted-by":"publisher"}],"name":"Nuffield Department of Clinical Neurosciences, Oxford Parkinson\u2019s Disease Center, University of 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