Mendelian forms of Parkinson's disease.

Over the last few years, genetic findings have changed our views on Parkinson's disease (PD), as mutations in a growing number of genes are found to cause monogenic forms of the disorder. Point mutations in the gene for alpha-synuclein, as well as duplications and triplications of the wild-type gene cause a dominant form of PD in rare families, pointing towards mishandling of this protein as a crucial step in the molecular pathogenesis of the disorder. Mutations in the gene for leucine-rich repeat kinase 2 (LRRK2) have recently been identified as a much more common cause for dominant PD, while mutations in the parkin gene, in DJ-1, PINK1 and ATP13A2 all cause autosomal-recessive parkinsonism of early onset. Mutations in recessive genes probably are pathogenic through loss-of-function mechanisms, suggesting that their wild-type products protect dopaminergic cells against a variety of insults. Evidence is emerging that at least some of these genes may play a direct role in the etiology of the common sporadic form of PD. Further, it is likely that the cellular pathways identified in rare monogenic variants of the disease also shed light on the molecular pathogenesis in typical sporadic PD.