PARK7 is an autosomal recessive familial PD caused by mutations of DJ-1 (Bonifati et al., 2003). Clinical features are essentially simi lar to those of PARK2 including the age of onset, which is younger than that of PARK6. Affected patients show L-dopa-responsive parkinsonism of varying severity and drug-induced motor fluctuation and dyskinesia. Interestingly, three out of four patients in the original family showed psychiatric disturbances (anxiety attacks) (Dekker et al., 2003). Atypical clinical features include short statue and brachydactyly, which were found in Dutch kindred (Dekker et al., 2004).
DJ-1 has been mapped to the short arm of chromosome 1 at 1p36 and was identified as a novel oncogene that transformed mouse NIH3T3 cells in cooperation with activated Ras (Nagakubo et al., 1997). To date, 6 missense mutations, 1 intronic mutation, 1 small deletion, and 2 exonic deletions (exon 1 to 5 and exon 5 to 7) are known (Bonifati et al., 2003; Abou-Sleiman et al., 2003; Hague et al., 2003; Hering et al., 2004) (Fig. 6). DJ-1 mutations are rare compared with parkin and PINK1 mutations. We could not find DJ-1 mutations among Japanese PD families studied.
DJ-1 is a potent anti-oxidative protein and this character depends on its 106-cysteine residue (Taira et al., 2004). DJ-1 is a cytoplas-
mic protein (Bonifati et al., 2003); however, oxidized DJ-1 is relocated to mitochondria (Canet-Aviles et al., 2004). DJ-1 undergoes dimmer formation to become active (Honbou et al., 2003; Tao and Tong, 2003). One of the PD-inducing missense mutations, L166P, interferes with dimmer formation (Wilson et al., 2003) and is degraded more rapidly than wild DJ-1 by ubiquitin-proteasome-system (Macedo et al., 2003; Miller et al., 2003) or by autoproteolysis (Gorner et al., 2004). This mutant DJ-1 is also mislocalized to mitochondria. Further interestingly, parkin interacts with mutated DJ-1 (L166P) but not with wild one (Moore et al., 2005), suggesting that parkin might be acting as a quality control protein for DJ-1. Thus molecular mechanism of nigral neuronal death in PARK7 appears to be at least in part related to dysfunction of anti-oxidative property of DJ-1.
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