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The secreted \u03b1\u2010syn can exhibit \u201cprion\u2010like\u201d behavior and transmission to na\u00efve cells can promote conformational changes and pathology. The precise role of plasma membrane proteins in the pathologic process of \u03b1\u2010syn is yet to be fully resolved. The TMEM16 family of lipid scramblases and ion channels has been recently associated with cancer and infectious diseases but is less known for its role in aging\u2010related diseases. To elucidate the role of TMEM16F in \u03b1\u2010syn spread, we transduced neurons derived from TMEM16F knockout mice with a reporter system that enables the distinction between donor and recipient neurons of pathologic \u03b1\u2010synA53T. We found that the spread of \u03b1\u2010synA53T was reduced in neurons derived from TMEM16F\u2010knockout mice. These findings were recapitulated in\u00a0vivo in a mouse model of PD, where attenuated \u03b1\u2010synA53T spread was observed when TMEM16F was ablated. Moreover, we identified a single nucleotide polymorphism in TMEM16F of Ashkenazi Jewish PD patients resulting in a missense Ala703Ser mutation with enhanced lipid scramblase activity. This mutation is associated with altered regulation of \u03b1\u2010synA53T extracellular secretion in cellular models of PD. Our study highlights TMEM16F as a novel regulator of \u03b1\u2010syn spread and as a potential therapeutic target in synucleinopathies.<\/jats:p>","DOI":"10.1111\/acel.14387","type":"journal-article","created":{"date-parts":[[2024,11,2]],"date-time":"2024-11-02T16:39:14Z","timestamp":1730565554000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["<scp>TMEM16F<\/scp> regulates pathologic \u03b1\u2010synuclein secretion and spread in cellular and mouse models of Parkinson's disease"],"prefix":"10.1111","volume":"24","author":[{"given":"Stav","family":"Cohen\u2010Adiv","sequence":"first","affiliation":[{"name":"The Department of Cell and Developmental Biology, Faculty of Medical and Health Sciences Tel Aviv University  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatima","family":"Amer\u2010Sarsour","sequence":"additional","affiliation":[{"name":"The Department of Cell and Developmental Biology, Faculty of Medical and Health Sciences Tel Aviv University  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yevgeny","family":"Berdichevsky","sequence":"additional","affiliation":[{"name":"The Department of Cell and Developmental Biology, Faculty of Medical and Health Sciences Tel Aviv University  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Boxer","sequence":"additional","affiliation":[{"name":"The School of Neurobiology, Biochemistry and Biophysics, the George S. 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