The Parkinson's Disease Susceptibility Gene PARK2 May Also Function as a Tumor Suppressor

Parkinson's disease is a movement disorder triggered by the loss of dopaminergic neurons in the area of the midbrain known as the substantia nigra. PARK2 is a gene implicated in the development of early-onset Parkinson's when mutated. Such mutations cause a loss of function of PARK2, which normally aids in the addition of ubiquiton to proteins to promote their degradation. However, a recent study published in NatureGenetics suggests that mutated PARK2 may also contribute to carcinogenesis when present in non-neuronal cells.

The authors used array comparative genomic hybridization to look for copy number changes of the PARK2 gene in glioblastoma, a form of brain cancer, and colon cancer samples. The authors focused on samples that had deletions on a specific area of chromosome 6, as this is frequently perturbed in cancer and contains the PARK2 gene itself. 85% of glioblastoma and 100% of colon cancer samples with alterations on chromosome 6 had a loss of PARK2 as well. Interestingly the authors discovered deletions in which PARK2 exons, termed "microdeletions", were specifically lost. This suggests that the area of chromosome 6 altered in cancer may selectively lose the PARK2 gene.

Next, the authors sequenced the PARK2 exons for all the samples, not just those with the chromosome 6 deletion, to look for DNA mutations. Samples for lung cancer were also included, in addition to colon and glioblastoma samples. The authors discovered numerous point mutations in the PARK2 gene and their individual contributions to cancer cell growth were assessed using numerous cancer cell lines.

Transfection of wild type PARK2 into glioblastoma (T98G), colon cancer (RKO), and lung cancer (NCI-H358 and NCI-H441) cells led to the prevention of colony formation in a colony formation assay. This suggest the introduction of PARK2 may reduce growth or promote cellular death of cancerous cells. However, transfection with mutated PARK2 (4 different PARK2 mutations were assessed) did not reduce colony formation. Similarly, tumor formation by cancerous glioma cells injected into mice was prevented by wild type PARK2, but not by the mutants. This suggests that PARK2 may function as a tumor suppressor in certain forms of cancer.

The authors work is significant in that it demonstrates that mutation of the PARK2 gene can have different consequences in different organs and cell types: Parkinson's disease in neuronal tissue of the brain and cancer in the colon, lung, and non-neuronal cells of the brain. Secondly, it provides yet more knowledge of another pathway selectively perturbed in cancer.

References:

Veeriah, S. et, al. Nature Genetics. 2010. 42 (1): 77-83