Objective: The aim was to test an association of rs6812193 and rs8475 of the SCARB2 gene with Parkinson’s disease (PD) in case–control study in Russia.

Background: Last findings demonstrated that lysosomal abnormalities may play a pivotal role in the common neurodegenerative disease as Parkinson’s disease (PD) due to impaired alpha-synuclein catabolism [1,2]. SCARB2 encodes lysosomal integral membrane protein type 2 (LIMP-2) involved in trafficking of enzyme glucocerebrosidase to the lysosomes. So SCARB2 is an attractive candidate gene for PD. Genome wide association study (GWAS) revealed rs6812193 of the SCARB2 gene as a risk factor for (PD) [2]. Interesting to note that there are no publications about association of rs8475 SCARB2 with any disease.

Method: rs6812193 and rs8475 of the SCARB2 gene  were genotypes in a total of  542 PD patients with negative family historyand 414 neurological healthy individuals (controls). Mononuclear CD45+ peripheral blood cells of studied individuals were immunomagnetically selected by magnetic cell sorting system (Miltenyi Biotec). SCARB2 mRNA  level were analyzed by real-time PCR with TaqMan assay. mRNA level of SCARB2 was normalized to the GNB2L1 and ACTBgenes.

Results: Logistic regression analysis demonstrated increased PD risk for TT variant rs8475 of SCARB2 (OR=1.97; 95%CI:1.435739-2.7197795, p<0.0001) while no statistically differences of genotypes distribution or allele frequencies of rs6812193 were found among PD patients and controls (p=0.663). Kaplan–Meier survival analysis and Cox regression revealed no association rs6812193 and rs8475 of SCARB2 gene with age at onset (AAO) of PD (p>0.05). There was no significant difference of SCARB2 expression level in CD45+ blood cells of PD patients and controls (p>0.05). SCARB2 expression level do not associate with rs6812193 and rs8475 of SCARB2 in all studied groups.

Conclusion: The current study first revealed the association rs8475 of the SCARB2 gene with PD. TT variant of rs8475 of the SCARB2gene increase twice risk of PD. rs6812193 and rs8475 polymorphisms of SCARB2 are not genetic modifier of AAO of PD and do not influence on SCARB2 expression levels in CD45+ blood cells. The study was supported by the Russian Science Foundation grant No. 19-15-00315.

References: 1. Klein A.D., Mazzulli J.R. Is Parkinson’s disease a lysosomal disorder. Brain, 2018. 141. P. 2255-2262. 2. Senkevich K, Gan-Or Z. Autophagy lysosomal pathway dysfunction in Parkinson’s disease; evidence from human genetics. Parkinsonism Relat Disord. 2019 Nov 17.pii: S1353-8020(19)30491-2. 3. Do CB, Tung JY, Dorfman E, Kiefer AK, Drabant EM, Francke U, Mountain JL, Goldman SM, Tanner CM, Langston JW, Wojcicki A, Eriksson N. Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson’s disease. PLoS Genet. 2011(7):e1002141.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/mrna-level-and-variants-of-the-scarb2-gene-in-the-pathogenesis-of-parkinsons-disease/