Category: Parkinson's Disease: Genetics
Objective: To examine whether the activity of the lysosomal enzyme glucocerebrosidase (GCase) is associated with LRRK2 variants.
Background: Mutations in GBA (which encodes GCase) and LRRK2 are the most common genetic risk factors in Parkinson’s disease (PD). We previously reported higher GCase enzymatic activity, as measured in dried blood spots, in carriers of the LRRK2 p.G2019S variant compared to non-carriers. However, in dopaminergic neurons with LRRK2 variants (p.G2019S, p.R1441G, p.R1441C), the activity of GCase was decreased.
Method: Full sequencing of LRRK2 and GBA was performed in PD (n=951) and in controls (n=487) recruited at Columbia University, NY. Logistic regression models adjusted for age, sex and ancestry were performed for common variants to analyse association with PD. Measurement of GCase activity was performed in 760 participants (511 PD patients and 249 controls) at Sanofi laboratories by liquid chromatography-tandem mass spectrometry (LC-MS/MS) from dried blood spots. Carriers of GBA variants (n=103) were excluded from analysis. Linear regression was used to test the association between LRRK2 variants and GCase activity, adjusting for age, sex, and PD status.
Results: We identified 24 common variants (MAF>1%) in LRRK2 including 9 nonsynonymous variants, 10 intronic variants and 5 synonymous variants. Among the nonsynonymous variants, in addition to previously reported increased activity in p.G2019S carriers, activity was significantly higher in p.N2081D carriers (13.35 µmol/l/h versus 11.79 µmol/l/h, p=0.006, Table 1); however, p.N2081D variant status was not associated with risk for PD (n in PD = 72, 7.6% versus n in controls = 32, 6.6%; p=0.4).
Conclusion: The LRRK2 p.G2019S and p.N2081D variants are associated with increased GCase activity. Additional studies are required to determine whether the p.N2081D variant is associated with risk for PD.
To cite this abstract in AMA style:K. Senkevich, E. Yu, L. Krohn, U. Rudakou, J. Ruskey, F. Asayesh, K. Mufti, S. Laurent, D. Spiegelman, S. Fahn, C. Waters, P. Sardi, G. Rouleau, R. Alcalay, Z. Gan-Or. LRRK2 p.G2019S and p.N2081D variants as modifiers of glucocerebrosidase activity [abstract]. Mov Disord. 2020; 35 (suppl 1). https://www.mdsabstracts.org/abstract/lrrk2-p-g2019s-and-p-n2081d-variants-as-modifiers-of-glucocerebrosidase-activity/. Accessed December 7, 2023.
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