The lysosomal enzyme alpha-Galactosidase A is deficient in Parkinson's disease brain in association with the pathologic accumulation of alpha-synuclein.

ABSTRACT: The aberrant accumulation of alpha-synuclein (?-syn) is believed to contribute to the onset and pathogenesis of Parkinson's disease (PD). The autophagy-lysosome pathway (ALP) is responsible for the high capacity clearance of ?-syn. ALP dysfunction is documented in PD and pre-clinical evidence suggests that inhibiting the ALP promotes the pathological accumulation of ?-syn. We previously identified the pathological accumulation of ?-syn in the brains of mice deficient for the soluble lysosomal enzyme alpha-Galactosidase A (?-Gal A), a member of the glycosphingolipid metabolism pathway. In the present study, we quantified ?-Gal A activity and levels of its glycosphingolipid metabolites in postmortem temporal cortex specimens from control individuals and in PD individuals staged with respect to ?-syn containing Lewy body pathology. In late-state PD temporal cortex we observed significant decreases in ?-Gal A activity and the 46kDa "active" species of ?-Gal A as determined respectively by fluorometric activity assay and western blot analysis. These decreases in ?-Gal A activity/levels correlated significantly with increased ?-syn phosphorylated at serine 129 (p129S-?-syn) that was maximal in late-stage PD temporal cortex. Mass spectrometric analysis of 29 different isoforms of globotriaosylceramide (Gb3), a substrate of ?-Gal A indicated no significant differences with respect to different stages of PD temporal cortex. However, significant correlations were observed between increased levels of several Gb3 isoforms and with decreased ?-Gal A activity and/or increased p129S-?-syn. Deacylated Gb3 (globotriaosylsphingosine or lyso-Gb3) was also analyzed in PD brain tissue but was below the limit of detection of 20pmol/g. Analysis of other lysosomal enzymes revealed a significant decrease in activity for the lysosomal aspartic acid protease cathepsin D but not for glucocerebrosidase (GCase) or cathepsin B in late-stage PD temporal cortex. However, a significant correlation was observed between decreasing GCase activity and increasing p129S-?-syn. Together our findings indicate ?-Gal A deficiency in late-stage PD brain that correlates significantly with the pathological accumulation of ?-syn, and further suggest the potential for ?-Gal A and its glycosphingolipid substrates as putative biomarkers for PD.

SUBMITTER: Nelson MP 

PROVIDER: S-EPMC5747987 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature