The lysosomal enzyme alpha-Galactosidase A is deficient in Parkinson's disease brain in association with the pathologic accumulation of alpha-synuclein.
The lysosomal enzyme alpha-Galactosidase A is deficient in Parkinson's disease brain in association with the pathologic accumulation of alpha-synuclein.
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DOI：
10.1016/j.nbd.2017.11.006
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发表时间：
2018-03
影响因子：
6.1
通讯作者：
Shacka JJ
中科院分区：
文献类型：
--
作者：
Nelson MP;Boutin M;Tse TE;Lu H;Haley ED;Ouyang X;Zhang J;Auray-Blais C;Shacka JJ
The aberrant accumulation of alpha-synuclein (α-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 α-syn. ALP dysfunction is documented in PD and pre-clinical evidence suggests that inhibiting the ALP promotes the pathological accumulation of α-syn. We previously identified the pathological accumulation of α-syn in the brains of mice deficient for the soluble lysosomal enzyme alpha-Galactosidase A (α-Gal A), a member of the glycosphingolipid metabolism pathway. In the present study, we quantified α-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 α-syn containing Lewy body pathology. In late-state PD temporal cortex we observed significant decreases in α-Gal A activity and the 46 kilodalton “active” species of α-Gal A as determined respectively by fluorometric activity assay and western blot analysis. These decreases in α-Gal A activity/levels correlated significantly with increased α-syn phosphorylated at serine 129 (p129S-α-syn) that was maximal in late-stage PD temporal cortex. Mass spectrometric analysis of 29 different isoforms of globotriaosylceramide (Gb3), a substrate of α-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 α-Gal A activity and/or increased p129S-α-syn. Deacylated Gb3 (globotriaosylsphingosine or lyso-Gb3) 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-α-syn. Together our findings indicate α-Gal A deficiency in late-stage PD brain that correlates significantly with the pathological accumulation of α-syn, and further suggest the potential for α-Gal A and its glycosphingolipid substrates as putative biomarkers for PD.
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影响因子：
3.7
作者：
Freeman D;Cedillos R;Choyke S;Lukic Z;McGuire K;Marvin S;Burrage AM;Sudholt S;Rana A;O'Connor C;Wiethoff CM;Campbell EM
通讯作者：
Campbell EM
影响因子：
4.7
作者：
Crabtree D;Dodson M;Ouyang X;Boyer-Guittaut M;Liang Q;Ballestas ME;Fineberg N;Zhang J
通讯作者：
Zhang J
影响因子：
15.1
作者：
Danzer KM;Kranich LR;Ruf WP;Cagsal-Getkin O;Winslow AR;Zhu L;Vanderburg CR;McLean PJ
通讯作者：
McLean PJ
影响因子：
7.4
作者：
Boutin, Michel;Sun, Ying;Auray-Blais, Christiane
通讯作者：
Auray-Blais, Christiane
影响因子：
6.1
作者：
Chu, Yaping;Dodiya, Hemraj;Kordower, Jeffrey H.
通讯作者：
Kordower, Jeffrey H.