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FUS mutations are associated with familial amyotrophic lateral sclerosis (fALS) and frontotemporal lobe degeneration (FTLD) in humans. At the molecular level, the mutated FUS protein is reduced in the nucleus but accumulates in cytoplasmic granules. Oligodendrocytes (OL) carrying clinically relevant FUS mutations contribute to non\u2010cell autonomous motor neuron disease progression, consistent with an extrinsic mechanism of disease mediated by OL. Knocking out FUS globally or in neurons lead to behavioral abnormalities that are similar to those present in FTLD. In this study, we sought to investigate whether an extrinsic mechanism mediated by loss of FUS function in OL contributes to the behavioral phenotype. We have generated a novel conditional knockout (cKO) in which <jats:italic>Fus<\/jats:italic> is selectively depleted in OL (<jats:italic>Fus<\/jats:italic><jats:sup>OL<\/jats:sup> cKO). The <jats:italic>Fus<\/jats:italic><jats:sup>OL<\/jats:sup> cKO mice show increased novelty\u2010induced motor activity and enhanced exploratory behavior, which are reminiscent of some manifestations of FTLD. The phenotypes are associated with greater myelin thickness, higher number of myelinated small diameter axons without an increase in the number of mature OL. The expression of the rate\u2010limiting enzyme of cholesterol biosynthesis (HMGCR) is increased in white matter tracts of the <jats:italic>Fus<\/jats:italic><jats:sup>OL<\/jats:sup>cKO and results in higher cholesterol content. In addition, phosphorylation of Akt, an important regulator of myelination is increased in the <jats:italic>Fus<\/jats:italic><jats:sup>OL<\/jats:sup>cKO. Collectively, this work has uncovered a novel role of oligodendrocytic <jats:italic>Fus<\/jats:italic> in regulating myelin deposition through activation of Akt and cholesterol biosynthesis.<\/jats:p>","DOI":"10.1002\/glia.23825","type":"journal-article","created":{"date-parts":[[2020,3,18]],"date-time":"2020-03-18T20:51:11Z","timestamp":1584564671000},"page":"2040-2056","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Conditional depletion of <i>Fus<\/i> in oligodendrocytes leads to motor hyperactivity and increased myelin deposition associated with Akt and cholesterol activation"],"prefix":"10.1002","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7066-1013","authenticated-orcid":false,"given":"Kelly M.","family":"Guzman","sequence":"first","affiliation":[{"name":"Research Department, Veterans Administration Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren E.","family":"Brink","sequence":"additional","affiliation":[{"name":"Research Department, Veterans Administration Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillermo","family":"Rodriguez\u2010Bey","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Graduate School of Public Health University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J.","family":"Bodnar","sequence":"additional","affiliation":[{"name":"Research Department, Veterans Administration Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisha","family":"Kuang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of Kentucky  Lexington Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Xing","sequence":"additional","affiliation":[{"name":"GE Healthcare  Waukesha Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mara","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Department of Cell Biology Center for Biologic Imaging, University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun J.","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Biostatistics and Biomedical Informatics School of Public Health University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Koppes","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Children's Hospital, UPMC  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haining","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of Kentucky  Lexington Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quasar","family":"Padiath","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Graduate School of Public Health University of Pittsburgh  Pittsburgh Pennsylvania USA"},{"name":"Department of Neurobiology University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3094-1501","authenticated-orcid":false,"given":"Franca","family":"Cambi","sequence":"additional","affiliation":[{"name":"Research Department, Veterans Administration Pittsburgh  Pittsburgh Pennsylvania USA"},{"name":"Department of Neurology\/PIND University of Pittsburgh  Pittsburgh Pennsylvania USA"},{"name":"Department of Neurology University of Kentucky  Lexington Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,3,18]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/1742-2094-10-146"},{"key":"e_1_2_8_3_1","volume-title":"Methods of behavior analysis in neuroscience","author":"Bailey K. 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