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Maturation of oligodendrocyte progenitor cells (OPC) to myelinating oligodendrocytes (OL), the sole providers of central nervous system (CNS) myelin, is tightly regulated and involves extensive morphological changes. Here, we present evidence that autophagy, the targeted isolation of cytoplasm and organelles by the double\u2010membrane autophagosome for lysosomal degradation, is essential for OPC\/OL differentiation, survival, and proper myelin development. A marked increase in autophagic activity coincides with OL differentiation, with OL processes having the greatest increase in autophagic flux. Multiple lines of evidence indicate that autophagosomes form in developing myelin sheathes before trafficking from myelin to the OL soma. Mice with conditional OPC\/OL\u2010specific deletion of the essential autophagy gene <jats:italic>Atg5<\/jats:italic> beginning on postnatal Day 5 develop a rapid tremor and die around postnatal Day 12. Further analysis revealed apoptotic death of OPCs, reduced differentiation, and reduced myelination. Surviving <jats:italic>Atg5<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> OLs failed to produce proper myelin structure. In vitro, pharmacological inhibition of autophagy in OPC\/dorsal root ganglion (DRG) co\u2010cultures blocked myelination, producing OLs surrounded by many short processes. Conversely, autophagy stimulation enhanced myelination. These results implicate autophagy as a key regulator of OPC survival, maturation, and proper myelination. Autophagy may provide an attractive target to promote both OL survival and subsequent myelin repair after injury.<\/jats:p>","DOI":"10.1002\/glia.23646","type":"journal-article","created":{"date-parts":[[2019,6,4]],"date-time":"2019-06-04T17:13:24Z","timestamp":1559668404000},"page":"1745-1759","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":105,"title":["Autophagy is essential for oligodendrocyte differentiation, survival, and proper myelination"],"prefix":"10.1002","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8354-1333","authenticated-orcid":false,"given":"Andrew N.","family":"Bankston","sequence":"first","affiliation":[{"name":"Kentucky Spinal Cord Injury Research Center University of Louisville School of Medicine  Louisville Kentucky"},{"name":"Department of Neurological Surgery University of Louisville School of Medicine  Louisville Kentucky"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"Forston","sequence":"additional","affiliation":[{"name":"Kentucky Spinal Cord Injury Research Center University of Louisville School of Medicine  Louisville Kentucky"},{"name":"Department of Anatomical Sciences &amp; Neurobiology University of Louisville School of Medicine  Louisville Kentucky"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell M.","family":"Howard","sequence":"additional","affiliation":[{"name":"Kentucky Spinal Cord Injury Research Center University of Louisville School of Medicine  Louisville Kentucky"},{"name":"Department of Neurological Surgery University of Louisville School of Medicine  Louisville Kentucky"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kariena R.","family":"Andres","sequence":"additional","affiliation":[{"name":"Kentucky Spinal Cord Injury Research Center University of Louisville School of Medicine  Louisville Kentucky"},{"name":"Department of Neurological Surgery University of Louisville School of Medicine  Louisville Kentucky"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison E.","family":"Smith","sequence":"additional","affiliation":[{"name":"Kentucky Spinal Cord Injury Research Center University of Louisville School of Medicine  Louisville Kentucky"},{"name":"Department of Neurological Surgery University of Louisville School of Medicine  Louisville Kentucky"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sujata Saraswat","family":"Ohri","sequence":"additional","affiliation":[{"name":"Kentucky Spinal Cord Injury Research Center University of Louisville School of Medicine  Louisville Kentucky"},{"name":"Department of Neurological Surgery University of Louisville School of Medicine  Louisville Kentucky"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret L.","family":"Bates","sequence":"additional","affiliation":[{"name":"The Miami Project to Cure Paralysis University of Miami Miller School of Medicine  Miami Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary B.","family":"Bunge","sequence":"additional","affiliation":[{"name":"The Miami Project to Cure Paralysis University of Miami Miller School of Medicine  Miami Florida"},{"name":"Department of Cell Biology and Neurological Surgery University of Miami Miller School of Medicine  Miami Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6437-7200","authenticated-orcid":false,"given":"Scott R.","family":"Whittemore","sequence":"additional","affiliation":[{"name":"Kentucky Spinal Cord Injury Research Center University of Louisville School of Medicine  Louisville Kentucky"},{"name":"Department of Neurological Surgery University of Louisville School of Medicine  Louisville Kentucky"},{"name":"Department of Anatomical Sciences &amp; Neurobiology University of Louisville School of Medicine  Louisville Kentucky"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,6,4]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00627-13"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12264-013-1321-3"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(92)90531-G"},{"key":"e_1_2_7_5_1","first-page":"7572","article-title":"Role of the oligodendroglial cytoskeleton in differentiation and myelination","volume":"50","author":"Bauer N. 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