Mutations and mechanism: howPINK1may contribute to risk of sporadic Parkinson’s disease

This scientific commentary refers to ‘Heterozygous PINK1 p.G411S increases risk of Parkinson’s disease via a dominant-negative mechanism’, by Puschmann et al. (doi:10.1093/brain/aww261) .The pathogenesis of Parkinson’s disease, in keeping with other common neurodegenerative diseases, is a complex interplay of genetic and environmental factors. Significant progress has been made in dissecting the genetic architecture of both rare monogenic and more common sporadic forms of the disease. Mutations in three genes, SNCA , LRRK2 and VPS35 , cause autosomal dominant Parkinson’s disease, while mutations in six genes cause autosomal recessive Parkinson’s disease/parkinsonism: PINK1 , PARK7 /DJ-1, PARK2 /PARKIN, PLA2G6 , ATP13A2 , and FBXO7 . Taken together, monogenic forms of Parkinson’s disease account for 30% of cases of familial disease and 3–5% of sporadic disease. Nonetheless much of our knowledge of the pathogenic pathways that lead to neuronal dysfunction and death has emerged from the identification of these genes. The discovery of the monogenic forms naturally posed the question of whether these genes also influence the risk of sporadic disease. If the same genes that can harbour highly penetrant mutations in Parkinson’s disease also contain risk variants for sporadic disease, this would provide a genetic and pathophysiological link between the mendelian and sporadic forms (Lesage and Brice, 2012). Several genome-wide association studies have independently identified SNCA and LRRK2 as risk loci for sporadic disease, thus linking the risk of sporadic Parkinson’s disease to that of the autosomal dominant forms (Nalls et al. , 2014). However, the mechanism by which a risk variant alters biological function and confers susceptibility to disease remains an essential missing piece of the puzzle. In this issue of Brain , Puschmann and co-workers examine whether a genetic variant in PINK1 contributes to the risk of sporadic disease, and explore the biological mechanism by which it …