PARK2 (Parkin)

The PARK2 locus was first described in Japanese families with autosomal recessive juvenile parkinsonism (Matsumine et al., 1997). Later studies identified mutations in the gene for parkin as responsible for PD in these families (Kitada et al., 1998), and this was subsequently confirmed in families around the world (Abbas et al., 1999; Lücking et al., 2000).

Mutations in the parkin gene are the most common cause of recessive, early onset PD (teens to twenties), and may also play a role in sporadic cases of PD. In addition to an earlier onset of PD, affected individuals with mutations in the parkin gene have a somewhat slower progression but are prone to greater L-DOPA-induced motor fluctuations and dyskinesia. Parkin-associated PD cases do not often exhibit Lewy body pathology, suggesting possible differences in pathogenic mechanisms compared to idiopathic PD (Gasser, 2009).

Parkin is an E3 ubiquitin ligase that covalently attaches poly-ubiquitin chains to its substrates, targeting those proteins for degradation by the ubiquitin-proteosome system (Shimura et al., 2000; Zhang et al., 2000). Mutations to parkin associated with PD are thought to bestow a loss-of-function, either by interfering with substrate binding or E3 ligase activity, resulting in accumulation of parkin substrate proteins which can lead to cell death (Cookson, 2005; Yang, 2009). Parkin interactions with the PARK6 gene PINK1 and the PARK7 gene DJ-1 have also been reported (Shiba et al., 2009; Um et al., 2009; Xiong et al., 2009).