PARK3, Ubiquitin Hydrolase-L1 and Other PD Loci

Recent progress in the genetic characterization of Parkinson's disease (PD) provides increasing evidence for genetic heterogeneity. Linkage analysis in some large families with autosomal dominant inheritance of the disease allows the identification of several gene loci (PARKl, PARK3, PARK4) with subsequent characterization of the first disease gene, a-synuclein (PARKl). In other families with early-onset PD and autosomal recessive inheritance, additional gene loci are identified (PARK2, PARK6, PARK7). Based on the fact that parkin ubiquitinates a-synuclein, a model of altered protein degradation as the cause for PD is proposed in this chapter. This model currently stimulates the genetic analysis of other candidate genes and leads to the identification of a mutation in the ubiquitin C terminal hydrolase-Ll gene (UCH-Ll). The identification of rare mutations in PD patients in potentially involved gene products of this pathway as in the neurofilament genes or in the a-synuclein interacting protein synphilin-1 is, in particular, intriguing. These studies are complemented by the first successful whole genome mapping approaches with indications for linkage on chromosome 5q, 8p, and 17q, respectively. Clinically, it becomes obvious that the phenotype is broader than previously anticipated.