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Gaucher disease is the most common lysosomal storage disease in the general population and the most common genetic disorder in Ashkenazi Jews, up to 6% of whom are carriers of GBA mutations ( Horowitz et al., 1999). In Gaucher disease, diminished glucocerebrosidase enzymatic activity accounts for glucocerebroside accumulation in the spleen, liver and bone marrow. GBA encodes the lysosomal enzyme glucocerebrosidase, a glucosylceramide hydrolase that plays an important role in sphingolipid degradation, especially in the macrophage/monocyte cell lineage. GBA heterozygotes Aharon-Peretz et al., 2004 Lwin et al., 2004 Halperin et al., 2006 Goker-Alpan et al., 2008 Bras et al., 2009 Kalinderi et al., 2009 Mitsui et al., 2009 Sidransky et al., 2009 Giraldo et al., 2011). patients with Gaucher disease Neudorfer et al., 1996 Mitsui et al., 2009), and in carriers of a single GBA mutation (i.e. This association has been established in patients with mutations in two GBA alleles (i.e. Mutations in the glucocerebrosidase ( GBA) gene are associated with Parkinson’s disease. Parkinson’s disease, glucocerebrosidase, lysosome, genetics, LRRK2 Introduction Taken together, these data suggest that glucocerebrosidase enzymatic activity could be a modifiable therapeutic target. High glucocerebrosidase enzymatic activity in LRRK2 G2019S carriers may reflect a distinct pathogenic mechanism. 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. We conclude that lower glucocerebrosidase enzymatic activity is strongly associated with GBA mutations, and modestly with idiopathic Parkinson’s disease. 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.
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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). 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). 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).
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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). 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). 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). 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. 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. 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. However, it is unknown whether the increased risk of Parkinson’s disease in GBA carriers is due to a loss of glucocerebrosidase enzymatic activity.
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Glucocerebrosidase ( GBA) mutations have been associated with Parkinson’s disease in numerous studies.