Genetic susceptibility of Parkinson's disease.

Abstract

Leucine-rich repeat kinase 2 (LRRK2) was identified as a causative gene in Parkinson’s disease. Met1646Thr (c.4937T>C, rs35303786) variant was recently found in Caucasian population. We therefore assessed the frequency of LRRK2 Met1646Thr variants in different ethnic groups to determine its ethnic specificity. We used chain terminator sequencing to identify variants in DNA samples from 216 Polish subjects. The frequency of Met1646Thr genotype was higher in patients compared to healthy controls (6.20% versus 3.00%, odds ratio = 2.21, 95% CI = 0.707 – 7.33). We did not find Met1646Thr variant in ethnic Chinese in Singapore, showing that this risk variant is ethnicity specific. In second part of the study, we compared the rate of apoptosis of stably transfected neuroblastoma cell lines harboring wild type LRRK2 or variants before and after oxidative stress treatment. Met1646Thr is associated with modestly increased neuronal cell death compared to wild type but this variant is weaker compared to the common pathogenic Gly2019Ser mutation. However, there was no significant increase in pro-apoptotic activity compared to wild type under oxidative stress. Animal models of Met1646Thr are needed to increase our knowledge of the pathophysiology of this variant, and genealogy studies may give us clues about the founding effects of this variant.