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Alpha galactosidase A activity in Parkinson's disease.
Neurobiol Dis. 2018 04; 112:85-90.ND

Abstract

Glucocerebrosidase (GCase, deficient in Gaucher disease) enzymatic activity measured in dried blood spots of Parkinson's Disease (PD) cases is within healthy range but reduced compared to controls. It is not known whether activities of additional lysosomal enzymes are reduced in dried blood spots in PD. To test whether reduction in lysosomal enzymatic activity in PD is specific to GCase, we measured GCase, acid sphingomyelinase (deficient in Niemann-Pick disease types A and B), alpha galactosidase A (deficient in Fabry), acid alpha-glucosidase (deficient in Pompe) and galactosylceramidase (deficient in Krabbe) enzymatic activities in dried blood spots of PD patients (n = 648) and controls (n = 317) recruited from Columbia University. Full sequencing of glucocerebrosidase (GBA) and the LRRK2 G2019S mutation was performed. Enzymatic activities were compared between PD cases and controls using t-test and regression models adjusted for age, gender, and GBA and LRRK2 G2019S mutation status. Alpha galactosidase A activity was lower in PD cases compared to controls both when only non-carriers were included (excluding all GBA and LRRK2 G2019S carriers and PD cases with age-at-onset below 40) [2.85 μmol/l/h versus 3.12 μmol/l/h, p = 0.018; after controlling for batch effect, p = 0.006 (468 PD cases and 296 controls)], and when including the entire cohort (2.89 μmol/l/h versus 3.10 μmol/l/h, p = 0.040; after controlling for batch effect, p = 0.011). Because the alpha galactosidase A gene is X-linked, we stratified the analyses by sex. Among women who were non-carriers of GBA and LRRK2 G2019S mutations (PD, n = 155; control, n = 194), alpha galactosidase A activity was lower in PD compared to controls (2.77 μmol/l/h versus 3.10 μmol/l/h, p = 0.044; after controlling for a batch effect, p = 0.001). The enzymatic activity of acid sphingomyelinase, acid alpha-glucosidase and galactosylceramidase was not significantly different between PD and controls. In non-carriers, most lysosomal enzyme activities were correlated, with the strongest association in GCase, acid alpha-glucosidase, and alpha galactosidase A (Pearson correlation coefficient between 0.382 and 0.532). In a regression model with all five enzymes among non-carriers (adjusted for sex and age), higher alpha galactosidase A activity was associated with lower odds of PD status (OR = 0.54; 95% CI:0.31-0.95; p = 0.032). When LRRK2 G2019S PD carriers (n = 37) were compared to non-carriers with PD, carriers had higher GCase, acid sphingomyelinase and alpha galactosidase A activity. We conclude that alpha galactosidase A may have a potential independent role in PD, in addition to GCase.

Authors+Show Affiliations

Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA. Electronic address: rna2104@columbia.edu.Translational Sciences, Sanofi R&D, Framingham, MA, USA.Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.Division of Human Genetics, Cincinnati Children's Hospital Medical Center and the Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.Division of Human Genetics, Cincinnati Children's Hospital Medical Center and the Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.Montréal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada; Department of Neurology & Neurosurgery, McGill University, Montreal, QC, Canada; Department of Human Genetics, McGill University, Montreal, QC, Canada.Montréal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada; Department of Neurology & Neurosurgery, McGill University, Montreal, QC, Canada; Department of Human Genetics, McGill University, Montreal, QC, Canada.Department of Pediatrics and Medicine, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.Translational Sciences, Sanofi R&D, Framingham, MA, USA.Translational Sciences, Sanofi R&D, Framingham, MA, USA.Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA; Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA.Translational Sciences, Sanofi R&D, Framingham, MA, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29369793

Citation

Alcalay, R N., et al. "Alpha Galactosidase a Activity in Parkinson's Disease." Neurobiology of Disease, vol. 112, 2018, pp. 85-90.
Alcalay RN, Wolf P, Levy OA, et al. Alpha galactosidase A activity in Parkinson's disease. Neurobiol Dis. 2018;112:85-90.
Alcalay, R. N., Wolf, P., Levy, O. A., Kang, U. J., Waters, C., Fahn, S., Ford, B., Kuo, S. H., Vanegas, N., Shah, H., Liong, C., Narayan, S., Pauciulo, M. W., Nichols, W. C., Gan-Or, Z., Rouleau, G. A., Chung, W. K., Oliva, P., Keutzer, J., ... Zhang, X. K. (2018). Alpha galactosidase A activity in Parkinson's disease. Neurobiology of Disease, 112, 85-90. https://doi.org/10.1016/j.nbd.2018.01.012
Alcalay RN, et al. Alpha Galactosidase a Activity in Parkinson's Disease. Neurobiol Dis. 2018;112:85-90. PubMed PMID: 29369793.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Alpha galactosidase A activity in Parkinson's disease. AU - Alcalay,R N, AU - Wolf,P, AU - Levy,O A, AU - Kang,U J, AU - Waters,C, AU - Fahn,S, AU - Ford,B, AU - Kuo,S H, AU - Vanegas,N, AU - Shah,H, AU - Liong,C, AU - Narayan,S, AU - Pauciulo,M W, AU - Nichols,W C, AU - Gan-Or,Z, AU - Rouleau,G A, AU - Chung,W K, AU - Oliva,P, AU - Keutzer,J, AU - Marder,K, AU - Zhang,X K, Y1 - 2018/02/02/ PY - 2017/12/18/received PY - 2018/01/16/revised PY - 2018/01/17/accepted PY - 2018/1/26/pubmed PY - 2019/9/7/medline PY - 2018/1/26/entrez KW - Biomarkers KW - Lysosomal storage disease KW - Movement disorders KW - Neurodegeneration KW - Parkinson's disease SP - 85 EP - 90 JF - Neurobiology of disease JO - Neurobiol Dis VL - 112 N2 - Glucocerebrosidase (GCase, deficient in Gaucher disease) enzymatic activity measured in dried blood spots of Parkinson's Disease (PD) cases is within healthy range but reduced compared to controls. It is not known whether activities of additional lysosomal enzymes are reduced in dried blood spots in PD. To test whether reduction in lysosomal enzymatic activity in PD is specific to GCase, we measured GCase, acid sphingomyelinase (deficient in Niemann-Pick disease types A and B), alpha galactosidase A (deficient in Fabry), acid alpha-glucosidase (deficient in Pompe) and galactosylceramidase (deficient in Krabbe) enzymatic activities in dried blood spots of PD patients (n = 648) and controls (n = 317) recruited from Columbia University. Full sequencing of glucocerebrosidase (GBA) and the LRRK2 G2019S mutation was performed. Enzymatic activities were compared between PD cases and controls using t-test and regression models adjusted for age, gender, and GBA and LRRK2 G2019S mutation status. Alpha galactosidase A activity was lower in PD cases compared to controls both when only non-carriers were included (excluding all GBA and LRRK2 G2019S carriers and PD cases with age-at-onset below 40) [2.85 μmol/l/h versus 3.12 μmol/l/h, p = 0.018; after controlling for batch effect, p = 0.006 (468 PD cases and 296 controls)], and when including the entire cohort (2.89 μmol/l/h versus 3.10 μmol/l/h, p = 0.040; after controlling for batch effect, p = 0.011). Because the alpha galactosidase A gene is X-linked, we stratified the analyses by sex. Among women who were non-carriers of GBA and LRRK2 G2019S mutations (PD, n = 155; control, n = 194), alpha galactosidase A activity was lower in PD compared to controls (2.77 μmol/l/h versus 3.10 μmol/l/h, p = 0.044; after controlling for a batch effect, p = 0.001). The enzymatic activity of acid sphingomyelinase, acid alpha-glucosidase and galactosylceramidase was not significantly different between PD and controls. In non-carriers, most lysosomal enzyme activities were correlated, with the strongest association in GCase, acid alpha-glucosidase, and alpha galactosidase A (Pearson correlation coefficient between 0.382 and 0.532). In a regression model with all five enzymes among non-carriers (adjusted for sex and age), higher alpha galactosidase A activity was associated with lower odds of PD status (OR = 0.54; 95% CI:0.31-0.95; p = 0.032). When LRRK2 G2019S PD carriers (n = 37) were compared to non-carriers with PD, carriers had higher GCase, acid sphingomyelinase and alpha galactosidase A activity. We conclude that alpha galactosidase A may have a potential independent role in PD, in addition to GCase. SN - 1095-953X UR - https://www.unboundmedicine.com/medline/citation/29369793/Alpha_galactosidase_A_activity_in_Parkinson's_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0969-9961(18)30018-4 DB - PRIME DP - Unbound Medicine ER -