{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T15:25:17Z","timestamp":1789226717982,"version":"build-2803163510"},"reference-count":49,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2019,10,23]],"date-time":"2019-10-23T00:00:00Z","timestamp":1571788800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["NS073994"],"award-info":[{"award-number":["NS073994"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["NS045962"],"award-info":[{"award-number":["NS045962"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["RR000165"],"award-info":[{"award-number":["RR000165"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["OD011132"],"award-info":[{"award-number":["OD011132"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["movementdisorders.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Movement Disorders"],"published-print":{"date-parts":[[2020,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Alpha\u2010synuclein (\u03b1\u2010syn) is a major component of Lewy bodies, which are the pathological hallmark in Parkinson's disease, and its genetic mutations cause familial forms of Parkinson's disease. Patients with \u03b1\u2010syn G51D mutation exhibit severe clinical symptoms. However, in vitro studies showed low propensity for \u03b1\u2010syn with the G51D mutation. We studied the mechanisms associated with severe neurotoxicity of \u03b1\u2010syn G51D mutation using a murine model generated by G51D \u03b1\u2010syn fibril injection into the brain.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Structural analysis of wild\u2010type and G51D \u03b1\u2010syn\u2010fibrils were performed using Fourier transform infrared spectroscopy. The ability of \u03b1\u2010syn fibrils forming aggregates was first assessed in in vitro mammalian cells. An in vivo mouse model with an intranigral injection of \u03b1\u2010syn fibrils was then used to evaluate the propagation pattern of \u03b1\u2010syn and related cellular changes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found that G51D \u03b1\u2010syn fibrils have higher \u03b2\u2010sheet contents than wild\u2010type \u03b1\u2010syn fibrils. The addition of G51D \u03b1\u2010syn fibrils to mammalian cells overexpressing \u03b1\u2010syn resulted in the formation of phosphorylated \u03b1\u2010syn inclusions at a higher rate. Similarly, an injection of G51D \u03b1\u2010syn fibrils into the substantia nigra of a mouse brain induced more widespread phosphorylated \u03b1\u2010syn pathology. Notably, the mice injected with G51D \u03b1\u2010syn fibrils exhibited progressive nigral neuronal loss accompanied with mitochondrial abnormalities and motor impairment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings indicate that the structural difference of G51D \u03b1\u2010syn fibrils plays an important role in the rapidly developed and more severe neurotoxicity of G51D mutation\u2010linked Parkinson's disease. \u00a9 2019 International Parkinson and Movement Disorder Society<\/jats:p><\/jats:sec>","DOI":"10.1002\/mds.27887","type":"journal-article","created":{"date-parts":[[2019,10,23]],"date-time":"2019-10-23T15:13:49Z","timestamp":1571843629000},"page":"256-267","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Structurally Distinct \u03b1\u2010Synuclein Fibrils Induce Robust Parkinsonian 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