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We recently reported that staufen1 (STAU1), a stress granule (SG) protein, was overabundant in fibroblast cell lines from patients with spinocerebellar ataxia type 2 (SCA2), amyotrophic lateral sclerosis, frontotemporal degeneration, Huntington's, Alzheimer's, and Parkinson's\u00a0diseases as well as animal models, and patient tissues. STAU1 overabundance is associated with mTOR hyperactivation and links SG formation with autophagy. Our objective was to determine the mechanism of mTOR regulation by STAU1.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We determined STAU1 abundance with disease\u2010 and chemical\u2010induced cellular stressors in patient cells and animal models. We also used RNA\u2010binding assays to contextualize STAU1 interaction with <jats:italic>MTOR<\/jats:italic> mRNA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>STAU1 and mTOR were overabundant in bacterial artificial chromosome (BAC)\u2010<jats:italic>C9ORF72<\/jats:italic>, <jats:italic>ATXN2<\/jats:italic><jats:sup><jats:italic>Q127<\/jats:italic><\/jats:sup>, and <jats:italic>Thy1<\/jats:italic>\u2010<jats:italic>TDP\u201043<\/jats:italic> transgenic mouse models. Reducing STAU1 levels in these mice normalized mTOR levels and activity and autophagy\u2010related marker proteins. We also saw increased STAU1 levels in HEK293 cells transfected to express C9ORF72\u2010relevant dipeptide repeats (DPRs). Conversely, DPR accumulations were not observed in cells treated by <jats:italic>STAU1<\/jats:italic> RNA interference (RNAi). Overexpression of STAU1 in HEK293 cells increased mTOR levels through direct <jats:italic>MTOR<\/jats:italic> mRNA interaction, activating downstream targets and impairing autophagic flux. Targeting mTOR by rapamycin or RNAi normalized STAU1 abundance in an SCA2 cellular model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>STAU1 interaction with mTOR drives its hyperactivation and inhibits autophagic flux in multiple models of neurodegeneration. Staufen, therefore, constitutes a novel target to modulate mTOR activity and autophagy, and for the treatment of neurodegenerative diseases. ANN NEUROL 2023;93:398\u2013416<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.26515","type":"journal-article","created":{"date-parts":[[2022,9,24]],"date-time":"2022-09-24T05:09:35Z","timestamp":1663996175000},"page":"398-416","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Staufen Impairs Autophagy in Neurodegeneration"],"prefix":"10.1002","volume":"93","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9845-3125","authenticated-orcid":false,"given":"Sharan","family":"Paul","sequence":"first","affiliation":[{"name":"Department of Neurology University of Utah  Salt Lake City UT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Warunee","family":"Dansithong","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Utah  Salt Lake City UT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mandi","family":"Gandelman","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Utah  Salt Lake City UT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karla P.","family":"Figueroa","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Utah  Salt Lake City UT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Zu","sequence":"additional","affiliation":[{"name":"Center for NeuroGenetics and Department of Molecular Genetics and Microbiology University of Florida  Gainesville FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura P. 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