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Mutations in the human Xq28 localized gene <jats:italic>RAB39B<\/jats:italic> have been associated with X\u2010linked neurodevelopmental defects including macrocephaly, intellectual disability, autism spectrum disorder (ASD), as well as rare cases of early\u2010onset Parkinson's disease (PD). Despite the finding that RAB39B regulates GluA2 trafficking and could thus influence synaptic \u03b1\u2010amino\u20103\u2010hydroxy\u20105\u2010methyl\u20104\u2010isoxazolepropionic acid receptor subunit composition, reasons for the wide\u2010ranging neuropathological consequences associated with RAB39B defects have been unclear. Recent studies have now unraveled possible mechanisms underlying the neuropathological roles of this brain\u2010enriched small GTPase. Studies in RAB39B knockout mice showed that RAB39B interacts with components of Class I phosphatidylinositol\u20103\u2010kinase (PI3K) signaling. In its absence, the PI3K\u2010AKT\u2010mechanistic target of rapamycin signaling pathway in neural progenitor cells (NPCs) is hyperactivated, which promotes NPC proliferation, leading to macrocephaly and ASD. Pertaining to early\u2010onset PD, a complex of C9orf72, Smith\u2013Magenis syndrome chromosome region candidate 8 and WD repeat domain 41 that functions in autophagy has been identified as a guanine nucleotide exchange factor of RAB39B. Here, recent findings that have shed light on our mechanistic understanding of RAB39B's role in neurodevelopmental and neurodegenerative pathologies are reviewed. Caveats and unanswered questions are also discussed, and future perspectives outlined.<\/jats:p>","DOI":"10.1002\/jcp.29962","type":"journal-article","created":{"date-parts":[[2020,8,6]],"date-time":"2020-08-06T22:32:18Z","timestamp":1596753138000},"page":"1579-1592","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["RAB39B's role in membrane traffic, autophagy, and associated neuropathology"],"prefix":"10.1002","volume":"236","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1925-636X","authenticated-orcid":false,"given":"Bor Luen","family":"Tang","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Yong Loo Lin School of Medicine National University of Singapore  Singapore"},{"name":"NUS Graduate School of Integrative Sciences and Engineering, National University of Singapore  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