The lysosomal enzyme alpha-Galactosidase A is deficient in Parkinson's disease brain in association with the pathologic accumulation of alpha-synuclein
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 s...
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2018-02-01
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Series: | Neurobiology of Disease |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996117302723 |
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language |
English |
format |
Article |
sources |
DOAJ |
author |
Michael P. Nelson Michel Boutin Tonia E. Tse Hailin Lu Emily D. Haley Xiaosen Ouyang Jianhua Zhang Christiane Auray-Blais John J. Shacka |
spellingShingle |
Michael P. Nelson Michel Boutin Tonia E. Tse Hailin Lu Emily D. Haley Xiaosen Ouyang Jianhua Zhang Christiane Auray-Blais John J. Shacka 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 Alpha-Galactosidase A Alpha-synuclein Globotriaosylceramide Glycosphingolipids Parkinson's disease Lysosome |
author_facet |
Michael P. Nelson Michel Boutin Tonia E. Tse Hailin Lu Emily D. Haley Xiaosen Ouyang Jianhua Zhang Christiane Auray-Blais John J. Shacka |
author_sort |
Michael P. Nelson |
title |
The lysosomal enzyme alpha-Galactosidase A is deficient in Parkinson's disease brain in association with the pathologic accumulation of alpha-synuclein |
title_short |
The lysosomal enzyme alpha-Galactosidase A is deficient in Parkinson's disease brain in association with the pathologic accumulation of alpha-synuclein |
title_full |
The lysosomal enzyme alpha-Galactosidase A is deficient in Parkinson's disease brain in association with the pathologic accumulation of alpha-synuclein |
title_fullStr |
The lysosomal enzyme alpha-Galactosidase A is deficient in Parkinson's disease brain in association with the pathologic accumulation of alpha-synuclein |
title_full_unstemmed |
The lysosomal enzyme alpha-Galactosidase A is deficient in Parkinson's disease brain in association with the pathologic accumulation of alpha-synuclein |
title_sort |
lysosomal enzyme alpha-galactosidase a is deficient in parkinson's disease brain in association with the pathologic accumulation of alpha-synuclein |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2018-02-01 |
description |
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 46kDa “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 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-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. |
topic |
Alpha-Galactosidase A Alpha-synuclein Globotriaosylceramide Glycosphingolipids Parkinson's disease Lysosome |
url |
http://www.sciencedirect.com/science/article/pii/S0969996117302723 |
work_keys_str_mv |
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doaj-e650fb2ac5fe4bd784e66871416f2ba92021-03-22T12:46:02ZengElsevierNeurobiology of Disease1095-953X2018-02-011106881The lysosomal enzyme alpha-Galactosidase A is deficient in Parkinson's disease brain in association with the pathologic accumulation of alpha-synucleinMichael P. Nelson0Michel Boutin1Tonia E. Tse2Hailin Lu3Emily D. Haley4Xiaosen Ouyang5Jianhua Zhang6Christiane Auray-Blais7John J. Shacka8Dept. Pathology, University of Alabama at Birmingham, Birmingham, AL, United StatesDivision of Medical Genetics, Department of Pediatrics, Centre de Recherche-CHUS, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, CanadaDept. Pathology, University of Alabama at Birmingham, Birmingham, AL, United States; Dept. Pharmacology & Toxicology, University of Alabama at Birmingham, Birmingham, AL, United StatesDept. Pathology, University of Alabama at Birmingham, Birmingham, AL, United StatesDept. Pathology, University of Alabama at Birmingham, Birmingham, AL, United States; Dept. Pharmacology & Toxicology, University of Alabama at Birmingham, Birmingham, AL, United StatesDept. Pathology, University of Alabama at Birmingham, Birmingham, AL, United StatesDept. Pathology, University of Alabama at Birmingham, Birmingham, AL, United States; Birmingham VA Medical Center, Birmingham, AL, United StatesDivision of Medical Genetics, Department of Pediatrics, Centre de Recherche-CHUS, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, CanadaDept. Pathology, University of Alabama at Birmingham, Birmingham, AL, United States; Dept. Pharmacology & Toxicology, University of Alabama at Birmingham, Birmingham, AL, United States; Birmingham VA Medical Center, Birmingham, AL, United States; Corresponding author at: Dept. Pharmacology & Toxicology, University of Alabama at Birmingham 1670 University Blvd, VH 257, Birmingham, AL 35294, United States.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 46kDa “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 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-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.http://www.sciencedirect.com/science/article/pii/S0969996117302723Alpha-Galactosidase AAlpha-synucleinGlobotriaosylceramideGlycosphingolipidsParkinson's diseaseLysosome |