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

NEUROBIOLOGY OF DISEASE

卷:110

Article

Nelson, Michael P.¹  Boutin, Michel²  Tse, Tonia E.^1,3  Lu, Hailin¹  Haley, Emily D.^1,3  Ouyang, Xiaosen¹  Zhang, Jianhua^1,4  Auray-Blais, Christiane²  Shacka, John J.^1,3,4 

[1] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA

[2] Univ Sherbrooke, Fac Med & Hlth Sci, Ctr Rech CHUS, Div Med Genet,Dept Pediat, Sherbrooke, PQ, Canada

[3] Univ Alabama Birmingham, Dept Pharmacol & Toxicol, 1670 Univ Blvd,VH 257, Birmingham, AL 35294 USA

[4] Birmingham VA Med Ctr, Birmingham, AL USA

关键词: Alpha-Galactosidase A;    Alpha-synuclein;    Globotriaosylceramide;    Glycosphingolipids;    Parkinson's disease;    Lysosome;   

DOI  :  10.1016/j.nbd.2017.11.006

来源: Elsevier

【 摘 要 】

The aberrant accumulation of alpha-synuclein (alpha-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 alpha-syn. ALP dysfunction is documented in PD and pre-clinical evidence suggests that inhibiting the ALP promotes the pathological accumulation of alpha-syn. We previously identified the pathological accumulation of alpha-syn in the brains of mice deficient for the soluble lysosomal enzyme alpha-Galactosidase A (alpha-Gal A), a member of the glycosphingolipid metabolism pathway. In the present study, we quantified alpha-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 alpha-syn containing Lewy body pathology. In late-state PD temporal cortex we observed significant decreases in alpha-Gal A activity and the 46 kDa active species of alpha-Gal A as determined respectively by fluorometric activity assay and western blot analysis. These decreases in alpha-Gal A activity/levels correlated significantly with increased alpha-syn phosphorylated at serine 129 (p129S-alpha-syn) that was maximal in late-stage PD temporal cortex. Mass spectrometric analysis of 29 different isoforms of globotriaosylceramide (Gb(3)), a substrate of alpha-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 Gb(3) isoforms and with decreased alpha-Gal A activity and/or increased p129S-alpha-syn. Deacylated Gb(3) (globotriaosylsphingosine or lyso-Gb(3)) was also analyzed in PD brain tissue but was below the limit of detection of 20 pmol/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-alpha-syn. Together our findings indicate alpha-Gal A deficiency in late-stage PD brain that correlates significantly with the pathological accumulation of alpha-syn, and further suggest the potential for alpha-Gal A and its glycosphingolipid substrates as putative biomarkers for PD.

【 授权许可】

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