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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,9,6]]},"abstract":"<jats:p>Physical activity provides clinical benefit in Parkinson\u2019s disease (PD). Irisin is an exercise-induced polypeptide secreted by skeletal muscle that crosses the blood\u2013brain barrier and mediates certain effects of exercise. Here, we show that irisin prevents pathologic \u03b1-synuclein (\u03b1-syn)-induced neurodegeneration in the \u03b1-syn preformed fibril (PFF) mouse model of sporadic PD. Intravenous delivery of irisin via viral vectors following the stereotaxic intrastriatal injection of \u03b1-syn PFF cause a reduction in the formation of pathologic \u03b1-syn and prevented the loss of dopamine neurons and lowering of striatal dopamine. Irisin also substantially reduced the \u03b1-syn PFF-induced motor deficits as assessed behaviorally by the pole and grip strength test. Recombinant sustained irisin treatment of primary cortical neurons attenuated \u03b1-syn PFF toxicity by reducing the formation of phosphorylated serine 129 of \u03b1-syn and neuronal cell death. Tandem mass spectrometry and biochemical analysis revealed that irisin reduced pathologic \u03b1-syn by enhancing endolysosomal degradation of pathologic \u03b1-syn. Our findings highlight the potential for therapeutic disease modification of irisin in PD.<\/jats:p>","DOI":"10.1073\/pnas.2204835119","type":"journal-article","created":{"date-parts":[[2022,8,31]],"date-time":"2022-08-31T13:49:28Z","timestamp":1661953768000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":132,"title":["Amelioration of pathologic \u03b1-synuclein-induced Parkinson\u2019s disease by irisin"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7241-4902","authenticated-orcid":false,"given":"Tae-In","family":"Kam","sequence":"first","affiliation":[{"name":"Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205"},{"name":"Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 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Zarbakhsh , Irisin protects the substantia nigra dopaminergic neurons in the rat model of Parkinson\u2019s disease. Iran. J. Basic Med. Sci. 22, 722\u2013728 (2019).","journal-title":"Iran. J. Basic Med. 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Amelioration of pathologic \u03b1-synuclein-induced Parkinson\u2019s disease by irisin. ProteomeXchange Consortium. http:\/\/proteomecentral.proteomexchange.org\/cgi\/GetDataset?ID=PXD032670. 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