In 1998, mutations in a newly identified gene, parkin (PARK2, chromosome 6q25.2-q27), were escribed in Japanese families segregating early-onset parkinsonism as an autosomal recessive trait (Kitada et al., 1998). Several clinical features distinguish parkin-linked parkinsonism from sporadic Parkinson's disease, such as the wide range of ages at onset, varying from early childhood to late adulthood, frequent dystonia and slow progression. 

Parkin belongs to a family of proteins with conserved ubiquitin like (UBL) and RING finger motifs and mutations in parkin cause autosomal recessive juvenile parkinsonism (Kitada T. et al.,1998). Parkin is one of the components of Lewy bodies (Schlossmacher MG et al., 2002). Genomic studies indicate that the parkin gene consists of 12 exons and the first reported AR-JP patients had deletions of exons 3–7 and exon 4 (Kitada T. et al.,1998). Further studies show that apart from exon deletions, point mutations are also found in AR-JP patients with most of the mutations concentrated in the RING finger domain (West A. et al, 2002). It was found that a wide variety of mutations in parkin including exon deletions,duplications or point mutations are a major cause of early-onset autosomal recessive parkinsonism (Abbas N. et al, 1999; Lucking CB. et al., 2000).

Parkin has been shown to be associated with actin filaments (Huynh DP.et al., 2000), and in situ hybridization studies show that parkin, UchL1 and α-synuclein mRNA have similar expression patterns (Staropoli JF. et al., 2003). Parkin is cleaved by caspases during apoptosis in neuroblastoma cells, but how this might relate to dopaminergic neuronal cell death in AR-JP patients is not clear (Kahns S, et al. 2002).Recently, parkin was reported to function as an ubiquitin protein-ligase (E3) in the ubiquitin pathway (Imai Y, Soda M, Takahashi R., 2000; Shimura H. et al., 2000; Zhang Y et al., 2000). Several proteins have been identified as substrates for parkin and include cell division controlrelated protein 1 (CDCrel-1), a glycosylated form of α-synuclein (α-SP22), parkin-associated endothelin-receptor-like receptor (Pael-R), cyclin E and the α-synuclein interacting protein, synphilin-1(Chung KK. et al., 2001; Imai Y, Soda M, Takahashi R, 2000; Shimura H. et al., 2001; Staropoli JF. et al., 2003; Zhang Y et al., 2000). CDCrel-1 belongs to the septin family. It contains a GTPase-domain and it may regulates synaptic vesicle release in the nervous system (Beites CL. et al.; 1999).

Parkin and α-synuclein might be linked together in a common pathway through α-SP22 (Shimura H. et al., 2001). Another substrate that links parkin and α-synuclein together in the common pathway is the α-synuclein interacting protein synphilin-1. Synphilin-1 was first isolated by yeast two hybrid screening using α-synuclein as a bait and it was shown to be one of components in the Lewy bodies (Engelender S. et al. 1999; Wadabayashi K. et al 2000). Later studies showed that synphilin-1 can interact with and be the direct substrate of parkin (Chung KK. et al., 2001). Interestingly, co-expression of parkin,α-synuclein and synphilin-1 result in the formation of ubiquitin positive Lewy body like inclusion body and familial linked mutations in parkin disrupt the ubiqutination of these Lewy body-like inclusions (Chung KK. et al., 2001).

Pael-R is another protein that is a substrate for parkin. When overexpressed,Pael-R tend to become unfolded, ubiquitinated and causes unfolded protein-induced cell death (Iami Y. et al., 2001). Parkin binds to and ubiquitinates Pael-R, which subsequently promotes the degradation of Pael-R. Co-expression of parkin and Pael-R protects against unfolded protein-induced cell death (Iami Y. et al., 2001). Interestingly, a recent report has shown that parkin forms a complex with CHIP (carboxyl terminus of the Hsc70-interacting protein), Hsp70 and Pael-R which provides further evidence that parkin might play a prominent role in the unfolded protein stress response in the endoplasmic reticulum (ER) (Iami Y. et al., 2002).

Parkin was also shown to bind to the F-box/WD repeat protein hSel-10 and Cullin-1, and the complex targets cyclin E for degradation (Staropoli JF. et al., 2003). It is also interesting that parkin seems to be able to protect neurons against kainate-induced excitotoxicity, but how this is related to PD is not clear (Staropoli JF. et al., 2003). Parkin has also been shown to protect against toxicity associated with mutant α-synuclein, which provides further evidence that parkin and α-synuclein are in a common pathological pathway in PD (Petrucelli L. et al.; 2002).

[OMIM] [LOCUS LINK] [Parkin Substrates] [RBR] [ARIADNE]