SCARB2 variants and glucocerebrosidase activity in Parkinson’s disease

• Published in: NPJ Parkinson's Disease 2016-03, Vol.2 (1), p.16004, Article 16004
• Main Authors: Alcalay, Roy N, Levy, Oren A, Wolf, Pavlina, Oliva, Petra, Zhang, Xiaokui Kate, Waters, Cheryl H, Fahn, Stanley, Kang, Un Jung, Liong, Christopher, Ford, Blair, Mazzoni, Pietro, Kuo, Sheng, Johnson, Amelie, Xiong, Lan, Rouleau, Guy A, Chung, Wendy K, Marder, Karen S, Gan-Or, Ziv
• Format: Article
• Language: English
• Subjects: 631/208/1516; 631/378/1689; Biomedical and Life Sciences; Biomedicine; Neurology; Neurosciences; Parkinson's disease
• ISSN: 2373-8057; 2373-8057
• DOI: 10.1038/npjparkd.2016.4

Mutations in glucocerebrosidase ( GBA ) are a common risk factor for Parkinson's disease (PD). The scavenger receptor class B member 2 ( SCARB2 ) gene encodes a receptor responsible for the transport of glucocerebrosidase (GCase) to the lysosome. Two common SNPs in linkage disequilibrium with SCARB2 , rs6812193 and rs6825004, have been associated with PD and Lewy Body Disease in genome-wide association studies. Whether these SNPs are associated with altered glucocerebrosidase enzymatic activity is unknown. Our objective was to determine whether SCARB2 SNPs are associated with PD and with reduced GCase activity. The GBA gene was fully sequenced, and the LRRK2 G2019S and SCARB2 rs6812193 and rs6825004 SNPs were genotyped in 548 PD patients and 272 controls. GCase activity in dried blood spots was measured by tandem mass spectrometry. We tested the association between SCARB2 genotypes and PD risk in regression models adjusted for gender, age, and LRRK2 G2019S and GBA mutation status. We compared GCase activity between participants with different genotypes at rs6812193 and rs6825004. Genotype at rs6812193 was associated with PD status. PD cases were less likely to carry the T allele than the C allele (OR=0.71; P =0.004), but GCase enzymatic activity was similar across rs6812193 genotypes (C/C: 11.88 μmol/l/h; C/T: 11.80 μmol/l/h; T/T: 12.02 μmol/l/h; P =0.867). Genotype at rs6825004 was not associated with either PD status or GCase activity. In conclusion, our results support an association between SCARB2 genotype at rs6812193 and PD, but suggest that the increased risk is not mediated by GCase activity. Genetic variants: Testing for mechanistic insight A variant in the gene SCARB2 that is associated with Parkinson's disease does not alter the activity of lysosomal enzyme glucocerebrosidase. SCARB2 encodes a membrane receptor that transports glucocerebrosidase to cellular organelles known as lysosomes. Mutations in the gene that encodes glucocerebrosidase are an important risk factor for Parkinson's disease. Roy Alcalay at the Colombia University Medical Center, United States, and colleagues investigated whether two common single nucleotide polymorphisms (SNPs) in SCARB2 that modify the risk of developing Parkinson's disease (rs6812193 and rs68250004) do so by regulating glucocerebrosidase activity. They compared the enzyme's activity in blood spots from 548 people with Parkinson's disease and 272 controls that had been genotyped for SCARB2 SNPs. Although the