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Recently, a dominant D252N mutation in TMEM106B was shown to cause hypomyelinating leukodystrophy. However, how TMEM106B regulates myelination is still unclear. Here we show that TMEM106B is expressed and localized to the lysosome compartment in oligodendrocytes. TMEM106B deficiency in mice results in myelination defects with a significant reduction of protein levels of proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG), the membrane proteins found in the myelin sheath. The levels of many lysosome proteins are significantly decreased in the TMEM106B-deficient Oli-neu oligodendroglial precursor cell line. TMEM106B physically interacts with the lysosomal protease cathepsin D and is required to maintain proper cathepsin D levels in oligodendrocytes. Furthermore, we found that TMEM106B deficiency results in lysosome clustering in the perinuclear region and a decrease in lysosome exocytosis and cell surface PLP levels. Moreover, we found that the D252N mutation abolished lysosome enlargement and lysosome acidification induced by wild-type TMEM106B overexpression. Instead, it stimulates lysosome clustering near the nucleus as seen in TMEM106B-deficient cells. Our results support that TMEM106B regulates myelination through modulation of lysosome function in oligodendrocytes.<\/jats:p>","DOI":"10.1093\/brain\/awaa154","type":"journal-article","created":{"date-parts":[[2020,4,29]],"date-time":"2020-04-29T15:44:19Z","timestamp":1588175059000},"page":"2255-2271","source":"Crossref","is-referenced-by-count":56,"title":["A role of the frontotemporal lobar degeneration risk factor TMEM106B in myelination"],"prefix":"10.1093","volume":"143","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4833-2659","authenticated-orcid":false,"given":"Tuancheng","family":"Feng","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University Ithaca, NY 14853, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9254-8836","authenticated-orcid":false,"given":"Rory R","family":"Sheng","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University Ithaca, NY 14853, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santiago","family":"Sol\u00e9-Dom\u00e8nech","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Ullah","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University Ithaca, NY 14853, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolai","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University Ithaca, NY 14853, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina S","family":"Mendoza","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University Ithaca, NY 14853, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura Camila Martinez","family":"Enriquez","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University Ithaca, NY 14853, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2486-9889","authenticated-orcid":false,"given":"Isabel Iscol","family":"Katz","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University Ithaca, NY 14853, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel H","family":"Paushter","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University Ithaca, NY 14853, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter M","family":"Sullivan","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University Ithaca, NY 14853, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaochun","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University Ithaca, NY 14853, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick R","family":"Maxfield","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, 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