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Glucocerebrosidase gene (GBA) mutations are the most common genetic contributor to Parkinson's Disease (PD) and are associated with decreased Glucocerebrosidase (GCase) enzymatic activity in PD. PD patients without GBA mutations also exhibit lower levels of GCase activity in the central nervous system (CNS) suggesting a potential contribution of the enzyme activity in disease pathogenesis, possibly by alteration of lysosomal function. α-synuclein, a protein with a central role in PD pathogenesis, has been shown to be secreted partly in association with exosomes. It is possible that a dysfunction of the endocytic pathway through GCase may result in altered exosome release of α-synuclein. The aim of this study was to examine whether manipulating GCase activity in vivo and in vitro could affect α-synuclein accumulation and secretion. GCase overexpression in vitro resulted in a significant decrease of exosome secretion. Chronic inhibition of GCase activity in vivo, by administration of the covalent inhibitor conduritol-B epoxide (CBE) in A53T-SNCA Tg mice significantly elevated intracellular oligomeric α-synuclein species. Importantly, GCase inhibition, induced a profound increase in the number of brain exosomes released, as well as exosome-associated α-synuclein oligomers. Finally, virus-mediated expression of mutant GBA in the mouse striatum increased α-synuclein secretion in the same region. Together, these results provide for the first time evidence that a decrease of GCase or overepression of mutant GCase in a chronic in vivo setting can affect α-synuclein secretion. Such effects may mediate enhanced propagation of α-synuclein, driving pathology in GBA-associated PD.
PMID: 29547959 [PubMed - as supplied by publisher]