Alpha galactosidase A activity in Parkinson's disease

R. N. Alcalay*, P. Wolf, O. A. Levy, U. J. Kang, C. Waters, S. Fahn, B. Ford, S. H. Kuo, N. Vanegas, H. Shah, C. Liong, S. Narayan, M. W. Pauciulo, W. C. Nichols, Z. Gan-Or, G. A. Rouleau, W. K. Chung, P. Oliva, J. Keutzer, K. MarderX. K. Zhang

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)85-90
Number of pages6
JournalNeurobiology of Disease
Volume112
DOIs
StatePublished - Apr 2018
Externally publishedYes

Funding

FundersFunder number
National Institutes of HealthR01NS39422, DoD PR161817, R01 NS101982, K02NS080915, R03 NS096494
National Institute of Neurological Disorders and StrokeR56NS036630
National Center for Research ResourcesUL1 RR024156
Michael J. Fox Foundation for Parkinson's Research036630, 1UL1 RR024156-01, U01NS052592
Brookdale Foundation
Columbia UniversityUL1 TR000040
Parkinsonfonden
Parkinson's Foundation

    Keywords

    • Biomarkers
    • Lysosomal storage disease
    • Movement disorders
    • Neurodegeneration
    • Parkinson's disease

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