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This intricate system of membrane trafficking between different compartments is tightly orchestrated by Ras analog in brain (RAB) GTPases and their effectors. Of the 66 members of the RAB family in humans, many have been implicated in neurodegenerative diseases and impairment of their functions contributes to cellular stress, protein aggregation, and death. Critically, RAB39B loss\u2010of\u2010function mutations are known to be associated with X\u2010linked intellectual disability and with rare early\u2010onset Parkinson's disease. Moreover, recent studies have highlighted altered RAB39B expression in idiopathic cases of several Lewy body diseases (LBDs). This review contextualizes the role of RAB proteins in LBDs and highlights the consequences of RAB39B impairment in terms of endosomal trafficking, neurite outgrowth, synaptic maturation, autophagy, as well as alpha\u2010synuclein homeostasis. Additionally, the potential for therapeutic intervention is examined via a discussion of the recent progress towards the development of specific RAB modulators. \u00a9 2021 The Authors. <jats:italic>Movement Disorders<\/jats:italic> published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society<\/jats:p>","DOI":"10.1002\/mds.28605","type":"journal-article","created":{"date-parts":[[2021,5,3]],"date-time":"2021-05-03T11:30:39Z","timestamp":1620041439000},"page":"1744-1758","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Dysfunction of <scp>RAB39B\u2010<\/scp>Mediated Vesicular Trafficking in Lewy Body Diseases"],"prefix":"10.1002","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8034-9880","authenticated-orcid":false,"given":"David J.","family":"Koss","sequence":"first","affiliation":[{"name":"Translational and Clinical Research Institute, Faculty of Medical 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