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Here, we report that prion infection and prion\u2010mimetic antibodies deplete the phosphoinositide kinase PIKfyve\u2014which controls endolysosomal maturation\u2014from mouse brains, cultured cells, organotypic brain slices, and brains of Creutzfeldt\u2010Jakob disease victims. We found that PIKfyve is acylated by the acyltransferases zDHHC9 and zDHHC21, whose juxtavesicular topology is disturbed by prion infection, resulting in PIKfyve deacylation and rapid degradation, as well as endolysosomal hypertrophy and activation of TFEB\u2010dependent lysosomal enzymes. A protracted unfolded protein response (UPR), typical of prion diseases, also induced PIKfyve deacylation and degradation. Conversely, UPR antagonists restored PIKfyve levels in prion\u2010infected cells. Overexpression of zDHHC9 and zDHHC21, administration of the antiprion polythiophene LIN5044, or supplementation with the PIKfyve reaction product PI(3,5)P\n                    <jats:sub>2<\/jats:sub>\n                    suppressed prion\u2010induced vacuolation and restored lysosomal homeostasis. Thus, PIKfyve emerges as a central mediator of vacuolation and neurotoxicity in prion diseases.\n                  <\/jats:p>","DOI":"10.15252\/emmm.202114714","type":"journal-article","created":{"date-parts":[[2021,7,22]],"date-time":"2021-07-22T03:26:21Z","timestamp":1626924381000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Loss of PIKfyve drives the spongiform degeneration in prion diseases"],"prefix":"10.1038","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8752-148X","authenticated-orcid":false,"given":"Asvin K K","family":"Lakkaraju","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0945-8857","authenticated-orcid":false,"given":"Karl","family":"Frontzek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4342-0940","authenticated-orcid":false,"given":"Emina","family":"Lemes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uli","family":"Herrmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3428-418X","authenticated-orcid":false,"given":"Marco","family":"Losa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajlakshmi","family":"Marpakwar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0344-6708","authenticated-orcid":false,"given":"Adriano","family":"Aguzzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,7,22]]},"reference":[{"key":"BFEMMM202114714_CR1","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1146\/annurev.pathmechdis.3.121806.154326","volume":"3","author":"A Aguzzi","year":"2008","unstructured":"Aguzzi A, Sigurdson C, Heikenwaelder M (2008) Molecular mechanisms of prion pathogenesis. 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