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Live-cell imaging and comparative transcriptomics demonstrates that the transcription factor EB (TFEB), an upstream regulator of lysosomal biogenesis, is activated upon treatment with AF38469. Utilizing CLN2 and CLN3 Batten disease mouse models, we performed a short-term efficacy study and show that treatment with AF38469 prevents the accumulation of lysosomal storage material and the development of neuroinflammation, key disease associated pathologies. Tremor phenotypes, an early behavioral phenotype in the CLN2 disease model, were also completely rescued. These findings reveal sortilin inhibition as a novel and highly efficacious therapeutic modality for the treatment of multiple forms of Batten disease.<\/jats:p>","DOI":"10.1101\/2023.09.22.559064","type":"posted-content","created":{"date-parts":[[2023,9,23]],"date-time":"2023-09-23T04:05:18Z","timestamp":1695441918000},"source":"Crossref","is-referenced-by-count":4,"title":["Sortilin inhibition treats multiple neurodegenerative lysosomal storage disorders"],"prefix":"10.64898","author":[{"given":"Hannah G.","family":"Leppert","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joelle T.","family":"Anderson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaylie J.","family":"Timm","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Davoli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melissa A.","family":"Pratt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clarissa D.","family":"Booth","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katherine A.","family":"White","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mitchell J.","family":"Rechtzigel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brandon L.","family":"Meyerink","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tyler B.","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jon J.","family":"Brudvig","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2504-4942","authenticated-orcid":false,"given":"Jill M.","family":"Weimer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023092705050625000_2023.09.22.559064v1.1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201208152"},{"key":"2023092705050625000_2023.09.22.559064v1.2","unstructured":"Fuller, M. ; Meikle, P. 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