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Fox Foundation for Parkinson's Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Acta Neuropathol"],"published-print":{"date-parts":[[2021,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Pathology consisting of intracellular aggregates of alpha-Synuclein (\u03b1-Syn) spread through the nervous system in a variety of neurodegenerative disorders including Parkinson\u2019s disease, dementia with Lewy bodies, and multiple system atrophy. The discovery of structurally distinct \u03b1-Syn polymorphs, so-called strains, supports a hypothesis where strain-specific structures are templated into aggregates formed by native \u03b1-Syn. These distinct strains are hypothesised to dictate the spreading of pathology in the tissue and the cellular impact of the aggregates, thereby contributing to the variety of clinical phenotypes. Here, we present evidence of a novel \u03b1-Syn strain induced by the multiple system atrophy-associated oligodendroglial protein p25\u03b1. Using an array of biophysical, biochemical, cellular, and in vivo analyses, we demonstrate that compared to \u03b1-Syn alone, a substoichiometric concentration of p25\u03b1 redirects \u03b1-Syn aggregation into a unique \u03b1-Syn\/p25\u03b1 strain with a different structure and enhanced in vivo prodegenerative properties. The \u03b1-Syn\/p25\u03b1 strain induced larger inclusions in human dopaminergic neurons. In vivo\n                    <jats:italic>,<\/jats:italic>\n                    intramuscular injection of preformed fibrils (PFF) of the \u03b1-Syn\/p25\u03b1 strain compared to \u03b1-Syn PFF resulted in a shortened life span and a distinct anatomical distribution of inclusion pathology in the brain of a human A53T transgenic (line M83) mouse. Investigation of \u03b1-Syn aggregates in brain stem extracts of end-stage mice demonstrated that the more aggressive phenotype of the \u03b1-Syn\/p25\u03b1 strain was associated with an increased load of \u03b1-Syn aggregates based on a F\u00f6rster resonance energy transfer immunoassay and a reduced \u03b1-Syn aggregate seeding activity based on a protein misfolding cyclic amplification assay. When injected unilaterally into the striata of wild-type mice, the \u03b1-Syn\/p25\u03b1 strain resulted in a more-pronounced motoric phenotype than \u03b1-Syn PFF and exhibited a \u201ctropism\u201d for nigro-striatal neurons compared to \u03b1-Syn PFF. Overall, our data support a hypothesis whereby oligodendroglial p25\u03b1 is responsible for generating a highly prodegenerative \u03b1-Syn strain in multiple system atrophy.\n                  <\/jats:p>","DOI":"10.1007\/s00401-021-02316-0","type":"journal-article","created":{"date-parts":[[2021,5,12]],"date-time":"2021-05-12T08:02:58Z","timestamp":1620806578000},"page":"87-115","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":85,"title":["Multiple system atrophy-associated oligodendroglial protein p25\u03b1 stimulates formation of novel \u03b1-synuclein strain with enhanced neurodegenerative potential"],"prefix":"10.1007","volume":"142","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0305-9097","authenticated-orcid":false,"given":"Nelson","family":"Ferreira","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hjalte","family":"Gram","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary A.","family":"Sorrentino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emil","family":"Gregersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sissel Ida","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lasse","family":"Reimer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristine","family":"Betzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Perez-Gozalbo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjo","family":"Beltoja","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madhu","family":"Nagaraj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan S.","family":"Nowak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingdong","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarina","family":"Will\u00e9n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ersoy","family":"Cholak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaare","family":"Bjerregaard-Andersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Mendez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prakruti","family":"Rabadia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Shahnawaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Soto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel E.","family":"Otzen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00dcmit","family":"Akbey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morten","family":"Meyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benoit I.","family":"Giasson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Romero-Ramos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4439-9020","authenticated-orcid":false,"given":"Poul Henning","family":"Jensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,12]]},"reference":[{"key":"2316_CR1","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.nbd.2017.05.014","volume":"105","author":"H Abdelmotilib","year":"2017","unstructured":"Abdelmotilib H, Maltbie T, Delic V, Liu Z, Hu X, Fraser KB et al (2017) alpha-Synuclein fibril-induced inclusion spread in rats and mice correlates with dopaminergic Neurodegeneration. 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