title: Glucocerebrosidase activity in Parkinson's disease with and without GBA mutations.
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.affiliation: 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.
authors.forename: Roy N
authors.initials: RN
authors.lastname: Alcalay
authors.affiliation: 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.
authors.forename: Oren A
authors.initials: OA
authors.lastname: Levy
authors.affiliation: 1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
authors.forename: Cheryl C
authors.initials: CC
authors.lastname: Waters
authors.affiliation: 1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
authors.forename: Stanley
authors.initials: S
authors.lastname: Fahn
authors.affiliation: 1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
authors.forename: Blair
authors.initials: B
authors.lastname: Ford
authors.affiliation: 1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
authors.forename: Sheng-Han
authors.initials: SH
authors.lastname: Kuo
authors.affiliation: 1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
authors.forename: Pietro
authors.initials: P
authors.lastname: Mazzoni
authors.affiliation: 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.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Pauciulo
authors.affiliation: 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.
authors.forename: William C
authors.initials: WC
authors.lastname: Nichols
authors.affiliation: 4 Montréal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.
authors.forename: Ziv
authors.initials: Z
authors.lastname: Gan-Or
authors.affiliation: 4 Montréal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.affiliation: 5 Department of Pediatrics and Medicine, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
authors.affiliation: 6 Global BioTherapeutics, Genzyme, a Sanofi company, Framingham, MA, USA.
authors.forename: Pavlina
authors.initials: P
authors.lastname: Wolf
authors.affiliation: 6 Global BioTherapeutics, Genzyme, a Sanofi company, Framingham, MA, USA.
authors.forename: Petra
authors.initials: P
authors.lastname: Oliva
authors.affiliation: 6 Global BioTherapeutics, Genzyme, a Sanofi company, Framingham, MA, USA.
authors.forename: Joan
authors.initials: J
authors.lastname: Keutzer
authors.affiliation: 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.
authors.forename: Karen
authors.initials: K
authors.lastname: Marder
authors.affiliation: 6 Global BioTherapeutics, Genzyme, a Sanofi company, Framingham, MA, USA.
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000368:Aged; D015331:Cohort Studies; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics*; D005838:Genotype; D005962:Glucosylceramidase / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007585:Jews / Q000235:genetics; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012720:Severity of Illness Index
chemical_list: C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D005962:Glucosylceramidase
keywords: LRRK2; Parkinson’s disease; genetics; glucocerebrosidase; lysosome