Role of mendelian genes in "sporadic" Parkinson's disease

The molecular mechanisms underlying neuronal degeneration leading to Parkinson's disease (PD) remain unknown. However, it is becoming increasingly clear that genetic factors contribute to its complex pathogenesis. In the past 15 years, the genetic basis of rare forms of PD with Mendelian inheritance, which represent no more than 10% of the cases, has been investigated. More than 18 loci, identified through linkage analysis or genome wide association studies (GWAS), and eight validated genes have been identified so far [parkin, PTEN-induced kinase 1 (PINK1), DJ-1, ATP13A2, SNCA, Leucine-rich repeat kinase 2 (LRRK2), as well as two recently identified possibly causative genes, vacuolar protein sorting 35 (VPS35) and eukaryotic translation initiation factor 4G1 (EIF4G1)]. Many studies have shed light on their implication not only in familial but also in sporadic forms of PD. Recent GWAS have provided convincing evidence that polymorphic variants in these genes also confer an increased risk for late-onset sporadic PD. In addition, heterozygous mutations in GBA have now been well-validated as susceptibility factors for PD. The role of the most relevant associated genes and risk factors in sporadic PD are discussed in this review.