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Throughout the neurodegenerative disease field, the ability of a single protein to give rise to multiple distinct clinical disorders is explained by the strain hypothesis, or the idea that the misfolded protein conformation determines the resulting disease. This was initially shown using transmission studies in cell lines and mouse models; more recently cryo-electron microscopy (cryo-EM) validated this idea by identifying distinct \u03b1-synuclein filament folds in brain tissues from patients with Parkinson\u2019s disease, multiple system atrophy (MSA), and juvenile-onset synucleinopathy. However, very little is known about the \u03b1-synuclein filament structures that form in animal models of these disorders, and thus their relevance to human disease and suitability as models for therapeutic development remains a question. Here we report the first atomic resolution cryo-EM structures of \u03b1-synuclein fibrils from an MSA patient sample before and after transmission to a transgenic mouse model of disease. Our findings indicate that while distinct adaptations occur during fibril replication in the mouse host, key structural facets are maintained, validating the merits of this transmission model for supporting preclinical research on MSA.<\/jats:p>","DOI":"10.64898\/2026.05.06.723086","type":"posted-content","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T17:00:32Z","timestamp":1778518832000},"source":"Crossref","is-referenced-by-count":2,"title":["Adaptation of \u03b1-synuclein fibrils following multiple system atrophy transmission to mice"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0322-5689","authenticated-orcid":false,"given":"Mylan","family":"Mayer","sequence":"first","affiliation":[{"name":"Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2639-1578","authenticated-orcid":false,"given":"Chase R.","family":"Khedmatgozar","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, & Pathology and Prion Research Center, Colorado State University, Fort Collins, CO, USA;"},{"name":"Department of Biology, University of Massachusetts Amherst, Amherst, MA, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianna","family":"Zinnen","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, & Pathology and Prion Research Center, Colorado State University, Fort Collins, CO, USA;"},{"name":"Cell and Molecular Biology Graduate Program, Colorado State University, Fort Collins, CO, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9973-2572","authenticated-orcid":false,"given":"Matthew P.","family":"Frost","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Massachusetts Amherst, Amherst, MA, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4211-2567","authenticated-orcid":false,"given":"Patricia M.","family":"Reis","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Massachusetts Amherst, Amherst, MA, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0800-1115","authenticated-orcid":false,"given":"Sara A. M.","family":"Holec","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, & Pathology and Prion Research Center, Colorado State University, Fort Collins, CO, USA;"},{"name":"Department of Biology, University of Massachusetts Amherst, Amherst, MA, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Dexter","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, & Pathology and Prion Research Center, Colorado State University, Fort Collins, CO, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9345-1462","authenticated-orcid":false,"given":"Arthur A.","family":"Melo","sequence":"additional","affiliation":[{"name":"Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Tse","sequence":"additional","affiliation":[{"name":"Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA;"},{"name":"Department of Neurology, University of California San Francisco, San Francisco, CA, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0842-4935","authenticated-orcid":false,"given":"Gregory E.","family":"Merz","sequence":"additional","affiliation":[{"name":"Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA;"},{"name":"Department of Neurology, University of California San Francisco, San Francisco, CA, USA;"},{"name":"Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4029-1968","authenticated-orcid":false,"given":"Amanda L.","family":"Woerman","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, & Pathology and Prion Research Center, Colorado State University, Fort Collins, CO, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026051411101077000_2026.05.06.723086v2.1","doi-asserted-by":"publisher","DOI":"10.1099\/0022-1317-73-2-329"},{"key":"2026051411101077000_2026.05.06.723086v2.2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.66.4.2096-2101.1992"},{"key":"2026051411101077000_2026.05.06.723086v2.3","unstructured":"Bartz, J. 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