Parkinson's disease: piecing together a genetic jigsaw.

The role of genetics in the pathogenesis of Parkinson's disease has been subject to debate for decades. In recent years, the discovery of five genes and several more loci has provided important insight into its molecular aetiology. Some Parkinson's disease genes possibly cause Parkinson's disease by protein aggregation. The presence of Lewy bodies in carriers of mutations in one gene and their absence in carriers of another, however, still point towards a complex pathogenic network, with Parkinson's disease as a common clinical end point. The recent identification of the fourth and fifth Parkinson's disease genes suggests multiple pathways-an impaired oxidative stress defence for mutations in DJ-1, and a defect in another signalling pathway for mutations in NR4A2. Despite knowledge of genetics in familial Parkinson's disease, our knowledge of the common, late-onset form of Parkinson's disease remains limited. In non-familial Parkinson's disease, genes and environment probably interact to give rise to the disease. We review advances in the genetics of Parkinson's disease, focusing on the monogenic forms and their clinical and population-genetic consequences.