6q26

AR-JP,LPRS2,PARK2,PDJ

Parkinsons Disease

Mutations in PARK2 are responsible of 50% of cases with autosomal recessive juvenile Parkinsonism (AR-JP). They also explain ~15% of the sporadic cases with onset before 45 (Lucking et al., 2000; Bonifati, 2012) and act as susceptibility alleles for late-onset forms of Parkinson disease (2% of cases) (Oliveira et al., 2003). Clinical features of PARK2 homozygous mutation carriers are generally indistinguishable from those of idiopathic PD patients with the exception of a clear drop in onset age. Typically PARK2 patients present the classic symptoms of PD (such as bradykinesia, rigidity, and tremor), disease onset before the age of 50 years and a slow disease progression. Although they respond well to levodopa treatment, they are more likely to develop treatment-induced motor complications earlier in the treatment (Nuytemans et al., 2010).

Alzheimer Disease

Lonskaya and colleagues investigated the role of parkin in postmortem brain tissues from 21 patients with Alzheimer Disease (AD) and 15 control subjects. They observed decreased parkin solubility in cortex of patients and parkin co-localization with intraneuronal amyloid-beta depositions (Aβ1-42) in the hippocampus and cortex. Parkin accumulation with intraneuronal Aβ and p-Tau was detected in autophagosomes in AD brains. By using a gene transfer animal model, the authors also demonstrated that the expression of wild type parkin facilitate autophagic clearance and promoted deposition of Aβ1-42 and p-Tau into the lysosome (Lonskaya et al., 2013). Parkin, therefore, may clear autophagic defects via autophagosome degradation.

Leprosy

Using a positional cloning strategy in 197 Vietnamese leprosy simplex families, Mira et al. found significant associations between leprosy and 17 markers in the 5-prime regulatory region shared by PARK2 and PACRG. They then confirmed these results in 587 Brazilian leprosy cases and 388 unaffected controls. RT-PCR analysis detected wide expression of both PARK2 and PACRG in tissues, and suggested that, in addition to the common bidirectional promoter, gene-specific transcriptional activators may be involved in regulating cell- and tissue-specific gene expression (Mira et al., 2004). In 2013, Alter et al. replicated these findings showing a susceptibility locus in the shared PARK2 and PACRG promoter region in a Vietnamese population. They also found that two SNPs (rs1333955 and rs2023004) were associated with susceptibility to leprosy in a northern Indian population (Alter et al., 2013).

Gliomas

Veeriah et al. provided evidence that PARK2 acts as a tumour suppressor gene in glioblastoma multiforme. Genetically, they detected PARK2 copy number loss in 53 of 216 glioblastomas and somatic point mutations in 7 glioblastomas specimens (Veeriah et al., 2010). The action of tumour suppressor gene for gliomas has been furthermore described by Yeo et al., who found parkin expression dramatically reduced in glioma cells, while its restoration promoted G(1) phase cell-cycle arrest and mitigated the proliferation rate (Yeo et al., 2012). Authors suggested the analysis of parkin pathway activation as predictive for the survival outcome of patients with glioma. The effects of PARK2 on tumour cell growth were also confirmed by Lin et al., who reported that PARK2 is frequently deleted and underexpressed in human gliomas, and that restoration of PARK2 significantly inhibited glioma cell growth (Lin et al., 2015).
An interesting transcriptional target of parkin is p53. Viotti et al. were able to demonstrate that parkin levels inversely correlate to brain tumour grade and p53 levels in oligodendrogliomas, mixed gliomas and glioblastomas, and established that p53 controls parkin promoter transactivation, mRNA and protein levels (Viotti et al., 2014).

Colon cancer

Microarray analysis revealed copy number loss in 24 of 98 colon cancers and different PARK2 somatic point mutations in 2 colon cancer cells lines (Veeriah et al., 2010). Additionally, in 100 primary colorectal carcinomas, Poulogiannis et al. demonstrated by array comparative genomic hybridization that 33% show PARK2 copy number loss (Poulogiannis et al., 2010). The PARK2 deletions are mostly focal, heterozygous, and show maximum incidence in exons 3 and 4. Deficiency in expression of PARK2 is significantly associated also with adenomatous polyposis coli (APC) deficiency in human colorectal cancer. Moreover, in the same study, interbreeding of Park2 heterozygous knockout mice with Apc(Min) mice resulted in a dramatic acceleration of intestinal adenoma development and increased polyp multiplicity.

Lung adenocarcinoma

Somatic homozygous deletions of exon 2 of the PARK2 gene were found in 2 lung adenocarcinoma cell lines, Calu-3 and H-1573, suggesting that the loss of this locus and the resulting changes in its expression are involved in the development of the tumour (Cesari et al., 2003). Additional germline and somatic deletions were also reported by Iwakawa et al. in five patients with lung adenocarcinoma and in 31/267 lung adenocarcinoma, indicating that somatic PARK2 mutations occur rarely in lung adenocarcinoma development, but germline mutations could contribute to tumour progression (Iwakawa et al., 2012). Very recently, Xiong et al. reported the PARK2 germline mutation c.823C>T (p.Arg275Trp) in a family with eight cases of lung cancer (Xiong et al., 2015).

Ovarian Cancer

Two different groups identified both PARK2 genetic alterations and downregulated expression in ovarian cancer. Cesari et al. detected two PARK2 truncating deletions in 3 of 20 ovarian tumour samples, supporting the hypothesis that hemizygous or homozygous deletions are responsible for the abnormal expression of PARK2 in tumour biopsies and tumour cell lines. They suggest that PARK2 may act as a tumour suppressor gene and may contribute to the initiation and/or progression of ovarian cancer (Cesari et al., 2003). Denison et al. found four cell lines and four primary tumours as heterozygous for the duplication or deletion of a Parkin exon. The analysis of Parkin protein expression revealed that most of the ovarian cancer cell lines and primary tumours had diminished or absent Parkin expression (Denison et al., 2003).

Other malignancies

Alterations or molecular defects involving the coding region of the gene (single nucleotide mutations, copy numbers, gene breakage), epigenetic mechanisms, the mRNA up or down regulation, the protein level and the abnormal splicing of PARK2 have been linked to a wide range of other human malignancies (i.e. acute lymphoblastic leukemia, chronic myeloid leukemia, clear cell renal cell carcinoma, hepatocellular carcinoma, head and neck squamous cell carcinoma, gastric cancer, pancreatic adenocarcinoma, breast cancer, bladder urothelial cancer, thyroid cancer, adenoid cystic carcinoma) (Xu et al., 2014).