Nonstandard abbreviations used: Parkinson disease (PD); dopamine (DA); Alzheimer disease (AD); autosomal recessive juvenile parkinsonism (AR-JP); parkin-associated endothelial-like receptor (Pael-R). southwest Netherlands revealed another locus (PARK7) on chromosome 1p36, which is genetically and clinically distinct from PARK6 (17). PARK8 is linked to chromosome 12p11. 2-q13. 1 and is inherited in an autosomal dominant fashion with partial penetrance (18). Neuropathologic examination of four patients revealed nigral degeneration without Lewy bodies (18). Kufor-Rakeb syndrome, an autosomal recessive nigro-striatal-pallidal-pyramidal neurodegenerative disorder, has been mapped to a 9-cM region of chromosome 1p36 and designated PARK9 (19). A recent Icelandic study suggests that genetic variability is a major contributor to PD in this population (20), and the locus was recently localized to a region on chromosome 1p32 and designated PARK10 (21). It is likely that there are other gene loci, as not all familial PD has been linked to the current loci. The identification of the genes for PARK1 (α-synuclein), PARK2 (parkin), and PARK7 (DJ-1) has led to new insights and direction in PD research and pathogenesis (see below). The identification of the other genes will undoubtedly shed much additional light on the molecular mechanisms of PD pathogenesis. Besides identifying genetic mutations that cause PD, recent genomic screens have also identified genetic factors that may be important in its development (20). In particular, linkage and mutation analysis indicates that the parkin gene, in addition to being a direct cause of PD, is influential in the development of early-onset PD (22). Multiple genetic factors appear to be important in the development of idiopathic late-onset PD. Four single-nucleotide polymorphisms in the tau gene are significantly associated with an increased risk of developing PD (23). Thus, the association of PD with the haplotype of tau and the evidence for linkage to that region of chromosome 17q suggest that tau, or a gene in linkage disequilibrium with tau, is a genetic risk factor for PD. Three large case-series studies also established a significant association between polymorphism of the tau gene and PD (24–26). Frontotemporal dementia with parkinsonism (FTDP) is caused, in part, by mutations in tau (27). Chromosome 9q also seems to be a region that incurs a genetic risk factor for PD (23). Other suggestive linkages have been identified on chromosomes 1, 3q, 5q, 8p, 10, and 16 (22, 28). Genes influencing the age of onset of PD may be linked to chromosome 1p and chromosomes 6 and 10 (29). Interestingly, the linkage on chromosome 10 also influences the age of onset of AD (29). Other work has suggested that environmental factors also play a role in the development of PD (30). It is likely that genetic susceptibility coupled with environmental exposure contributes to the development and manifestation of sporadic PD. α-Synuclein mutations

Mutations in the α-synuclein gene are clearly a very rare cause of PD (8). The first mutation identified was an A53T mutation resulting from a G→ A transition at position 209 (9). This mutation was originally found in the Contursi kindred and was also identified in several Greek kindreds. Recent haplotype analyses suggest that the Contursi kindred and the Greek kindreds share a common ancestor (31). Another mutation (A30P) resulting from a G→ C