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Glucocerebrosidase activity in Parkinson's disease with and without GBA mutations.
Brain 2015; 138(Pt 9):2648-58B

Abstract

Glucocerebrosidase (GBA) mutations have been associated with Parkinson's disease in numerous studies. However, it is unknown whether the increased risk of Parkinson's disease in GBA carriers is due to a loss of glucocerebrosidase enzymatic activity. We measured glucocerebrosidase enzymatic activity in dried blood spots in patients with Parkinson's disease (n = 517) and controls (n = 252) with and without GBA mutations. Participants were recruited from Columbia University, New York, and fully sequenced for GBA mutations and genotyped for the LRRK2 G2019S mutation, the most common autosomal dominant mutation in the Ashkenazi Jewish population. Glucocerebrosidase enzymatic activity in dried blood spots was measured by a mass spectrometry-based assay and compared among participants categorized by GBA mutation status and Parkinson's disease diagnosis. Parkinson's disease patients were more likely than controls to carry the LRRK2 G2019S mutation (n = 39, 7.5% versus n = 2, 0.8%, P < 0.001) and GBA mutations or variants (seven homozygotes and compound heterozygotes and 81 heterozygotes, 17.0% versus 17 heterozygotes, 6.7%, P < 0.001). GBA homozygotes/compound heterozygotes had lower enzymatic activity than GBA heterozygotes (0.85 µmol/l/h versus 7.88 µmol/l/h, P < 0.001), and GBA heterozygotes had lower enzymatic activity than GBA and LRRK2 non-carriers (7.88 µmol/l/h versus 11.93 µmol/l/h, P < 0.001). Glucocerebrosidase activity was reduced in heterozygotes compared to non-carriers when each mutation was compared independently (N370S, P < 0.001; L444P, P < 0.001; 84GG, P = 0.003; R496H, P = 0.018) and also reduced in GBA variants associated with Parkinson's risk but not with Gaucher disease (E326K, P = 0.009; T369M, P < 0.001). When all patients with Parkinson's disease were considered, they had lower mean glucocerebrosidase enzymatic activity than controls (11.14 µmol/l/h versus 11.85 µmol/l/h, P = 0.011). Difference compared to controls persisted in patients with idiopathic Parkinson's disease (after exclusion of all GBA and LRRK2 carriers; 11.53 µmol/l/h, versus 12.11 µmol/l/h, P = 0.036) and after adjustment for age and gender (P = 0.012). Interestingly, LRRK2 G2019S carriers (n = 36), most of whom had Parkinson's disease, had higher enzymatic activity than non-carriers (13.69 µmol/l/h versus 11.93 µmol/l/h, P = 0.002). In patients with idiopathic Parkinson's, higher glucocerebrosidase enzymatic activity was associated with longer disease duration (P = 0.002) in adjusted models, suggesting a milder disease course. We conclude that lower glucocerebrosidase enzymatic activity is strongly associated with GBA mutations, and modestly with idiopathic Parkinson's disease. The association of lower glucocerebrosidase activity in both GBA mutation carriers and Parkinson's patients without GBA mutations suggests that loss of glucocerebrosidase function contributes to the pathogenesis of Parkinson's disease. High glucocerebrosidase enzymatic activity in LRRK2 G2019S carriers may reflect a distinct pathogenic mechanism. Taken together, these data suggest that glucocerebrosidase enzymatic activity could be a modifiable therapeutic target.

Authors+Show Affiliations

1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA 2 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 rna2104@columbia.edu.1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA 2 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.1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.3 Division of Human Genetics, Cincinnati Children's Hospital Medical Center and the Department of Pediatrics; University of Cincinnati College of Medicine, Cincinnati, OH, USA.3 Division of Human Genetics, Cincinnati Children's Hospital Medical Center and the Department of Pediatrics; University of Cincinnati College of Medicine, Cincinnati, OH, USA.4 Montréal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.4 Montréal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.5 Department of Pediatrics and Medicine, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.6 Global BioTherapeutics, Genzyme, a Sanofi company, Framingham, MA, USA.6 Global BioTherapeutics, Genzyme, a Sanofi company, Framingham, MA, USA.6 Global BioTherapeutics, Genzyme, a Sanofi company, Framingham, MA, USA.1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA 2 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 7 Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA.6 Global BioTherapeutics, Genzyme, a Sanofi company, 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

26117366

Citation

Alcalay, Roy N., et al. "Glucocerebrosidase Activity in Parkinson's Disease With and Without GBA Mutations." Brain : a Journal of Neurology, vol. 138, no. Pt 9, 2015, pp. 2648-58.
Alcalay RN, Levy OA, Waters CC, et al. Glucocerebrosidase activity in Parkinson's disease with and without GBA mutations. Brain. 2015;138(Pt 9):2648-58.
Alcalay, R. N., Levy, O. A., Waters, C. C., Fahn, S., Ford, B., Kuo, S. H., ... Zhang, X. (2015). Glucocerebrosidase activity in Parkinson's disease with and without GBA mutations. Brain : a Journal of Neurology, 138(Pt 9), pp. 2648-58. doi:10.1093/brain/awv179.
Alcalay RN, et al. Glucocerebrosidase Activity in Parkinson's Disease With and Without GBA Mutations. Brain. 2015;138(Pt 9):2648-58. PubMed PMID: 26117366.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Glucocerebrosidase activity in Parkinson's disease with and without GBA mutations. AU - Alcalay,Roy N, AU - Levy,Oren A, AU - Waters,Cheryl C, AU - Fahn,Stanley, AU - Ford,Blair, AU - Kuo,Sheng-Han, AU - Mazzoni,Pietro, AU - Pauciulo,Michael W, AU - Nichols,William C, AU - Gan-Or,Ziv, AU - Rouleau,Guy A, AU - Chung,Wendy K, AU - Wolf,Pavlina, AU - Oliva,Petra, AU - Keutzer,Joan, AU - Marder,Karen, AU - Zhang,Xiaokui, Y1 - 2015/06/27/ PY - 2015/01/28/received PY - 2015/04/27/accepted PY - 2015/6/29/entrez PY - 2015/6/29/pubmed PY - 2015/11/17/medline KW - LRRK2 KW - Parkinson’s disease KW - genetics KW - glucocerebrosidase KW - lysosome SP - 2648 EP - 58 JF - Brain : a journal of neurology JO - Brain VL - 138 IS - Pt 9 N2 - Glucocerebrosidase (GBA) mutations have been associated with Parkinson's disease in numerous studies. However, it is unknown whether the increased risk of Parkinson's disease in GBA carriers is due to a loss of glucocerebrosidase enzymatic activity. We measured glucocerebrosidase enzymatic activity in dried blood spots in patients with Parkinson's disease (n = 517) and controls (n = 252) with and without GBA mutations. Participants were recruited from Columbia University, New York, and fully sequenced for GBA mutations and genotyped for the LRRK2 G2019S mutation, the most common autosomal dominant mutation in the Ashkenazi Jewish population. Glucocerebrosidase enzymatic activity in dried blood spots was measured by a mass spectrometry-based assay and compared among participants categorized by GBA mutation status and Parkinson's disease diagnosis. Parkinson's disease patients were more likely than controls to carry the LRRK2 G2019S mutation (n = 39, 7.5% versus n = 2, 0.8%, P < 0.001) and GBA mutations or variants (seven homozygotes and compound heterozygotes and 81 heterozygotes, 17.0% versus 17 heterozygotes, 6.7%, P < 0.001). GBA homozygotes/compound heterozygotes had lower enzymatic activity than GBA heterozygotes (0.85 µmol/l/h versus 7.88 µmol/l/h, P < 0.001), and GBA heterozygotes had lower enzymatic activity than GBA and LRRK2 non-carriers (7.88 µmol/l/h versus 11.93 µmol/l/h, P < 0.001). Glucocerebrosidase activity was reduced in heterozygotes compared to non-carriers when each mutation was compared independently (N370S, P < 0.001; L444P, P < 0.001; 84GG, P = 0.003; R496H, P = 0.018) and also reduced in GBA variants associated with Parkinson's risk but not with Gaucher disease (E326K, P = 0.009; T369M, P < 0.001). When all patients with Parkinson's disease were considered, they had lower mean glucocerebrosidase enzymatic activity than controls (11.14 µmol/l/h versus 11.85 µmol/l/h, P = 0.011). Difference compared to controls persisted in patients with idiopathic Parkinson's disease (after exclusion of all GBA and LRRK2 carriers; 11.53 µmol/l/h, versus 12.11 µmol/l/h, P = 0.036) and after adjustment for age and gender (P = 0.012). Interestingly, LRRK2 G2019S carriers (n = 36), most of whom had Parkinson's disease, had higher enzymatic activity than non-carriers (13.69 µmol/l/h versus 11.93 µmol/l/h, P = 0.002). In patients with idiopathic Parkinson's, higher glucocerebrosidase enzymatic activity was associated with longer disease duration (P = 0.002) in adjusted models, suggesting a milder disease course. We conclude that lower glucocerebrosidase enzymatic activity is strongly associated with GBA mutations, and modestly with idiopathic Parkinson's disease. The association of lower glucocerebrosidase activity in both GBA mutation carriers and Parkinson's patients without GBA mutations suggests that loss of glucocerebrosidase function contributes to the pathogenesis of Parkinson's disease. High glucocerebrosidase enzymatic activity in LRRK2 G2019S carriers may reflect a distinct pathogenic mechanism. Taken together, these data suggest that glucocerebrosidase enzymatic activity could be a modifiable therapeutic target. SN - 1460-2156 UR - https://www.unboundmedicine.com/medline/citation/26117366/Glucocerebrosidase_activity_in_Parkinson's_disease_with_and_without_GBA_mutations_ L2 - https://academic.oup.com/brain/article-lookup/doi/10.1093/brain/awv179 DB - PRIME DP - Unbound Medicine ER -