SCARB2 variants and glucocerebrosidase activity in Parkinson’s disease

Abstract

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.

Mutated ATP10B increases Parkinson’s disease risk by compromising lysosomal glucosylceramide export

“…1 mark P < 0.05, 2 marks P < 0.01, 3 marks P < 0.001, 4 marks P < 0.0001 been associated with changes in lysosomal ceramide levels, though the exact mechanisms are still unknown [57,64,69]. Additionally, compelling associations between PD and genes involved in or linked to sphingolipid metabolism are emerging from genetic studies, including SMPD1, GALC and SCARB2 [7,21,39]. Here, we identified ATP10B as a novel putative PD risk gene and key player in lysosomal functioning and sphingolipid metabolism.…”

Analysis of common and rare VPS13C variants in late onset Parkinson disease

“…This cohort was previously genotyped using the GWAS OmniExpress array, the ethnicity was confirmed using principal component analysis, and samples that were of different ethnicities were not included in this study. The second cohort was recruited in New York - Columbia University, and was previously described 11 . The majority of participants from New York are of European descent and 38% are Ashkenazi Jewish (AJ), 40% of PD patients and 35% of controls.…”

The Vicious Cycle Between α‐Synuclein Aggregation and Autophagic‐Lysosomal Dysfunction

“…Single‐nucleotide polymorphisms (SNPs) on SCARB2 , which encodes for lysosomal integral membrane protein 2 (LIMP‐2), a protein responsible for GCase trafficking, have been also shown to be linked to the onset of LB pathologies . Although no relevant changes in GCase activities were recently found in dried blood spots of PD patients carrying SCARB2 SNPs versus controls, homozygous mutations are known to be responsible for the onset of lysosomal disorders with a systemic reduction in GCase activity . Conversely, overexpression of LIMP‐2 enhanced α‐syn clearance and improved lysosomal activity of GCase in different cell lines overexpressing α‐syn …”