The Biochemistry of Parkinson's Disease*

Several genes have been identified for monogenic disorders that variably resemble Parkinson's disease. Dominant mutations in the gene encoding α-synuclein enhance the propensity of this protein to aggregate. As a consequence, these patients have a widespread disease with protein inclusion bodies in several brain areas. In contrast, mutations in several recessive genes (parkin, DJ-1, and PINK1) produce neuronal cell loss but generally without protein aggregation pathology. Progress has been made in understanding some of the mechanisms of toxicity: Parkin is an E3 ubiquitin ligase and DJ-1 and PINK1 appear to protect against mitochondrial damage. However, we have not yet fully resolved how the recessive genes relate to α-synuclein, or whether they represent different ways to induce a similar phenotype.