title: Loss of β-glucocerebrosidase activity does not affect alpha-synuclein levels or lysosomal function in neuronal cells.
abstract: To date, a plethora of studies have provided evidence favoring an association between Gaucher disease (GD) and Parkinson's disease (PD). GD, the most common lysosomal storage disorder, results from the diminished activity of the lysosomal enzyme β-glucocerebrosidase (GCase), caused by mutations in the β-glucocerebrosidase gene (GBA). Alpha-synuclein (ASYN), a presynaptic protein, has been strongly implicated in PD pathogenesis. ASYN may in part be degraded by the lysosomes and may itself aberrantly impact lysosomal function. Therefore, a putative link between deficient GCase and ASYN, involving lysosomal dysfunction, has been proposed to be responsible for the risk for PD conferred by GBA mutations. In this current work, we aimed to investigate the effects of pharmacological inhibition of GCase on ASYN accumulation/aggregation, as well as on lysosomal function, in differentiated SH-SY5Y cells and in primary neuronal cultures. Following profound inhibition of the enzyme activity, we did not find significant alterations in ASYN levels, or any changes in the clearance or formation of its oligomeric species. We further observed no significant impairment of the lysosomal degradation machinery. These findings suggest that additional interaction pathways together with aberrant GCase and ASYN must govern this complex relation between GD and PD.
authors.affiliation: Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors.forename: Georgia
authors.initials: G
authors.lastname: Dermentzaki
authors.forename: Evangelia
authors.initials: E
authors.lastname: Dimitriou
authors.forename: Maria
authors.initials: M
authors.lastname: Xilouri
authors.forename: Helen
authors.initials: H
authors.lastname: Michelakakis
authors.forename: Leonidas
authors.initials: L
authors.lastname: Stefanis
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D005776:Gaucher Disease / Q000235:genetics / Q000378:metabolism; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors / Q000172:deficiency*; D006801:Humans; D007294:Inositol / Q000031:analogs & derivatives / Q000494:pharmacology; D008247:Lysosomes / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D055503:Protein Multimerization; D051381:Rats; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein; D007294:Inositol; D005962:Glucosylceramidase; C011423:conduritol epoxide