PARK2

The PARK2 gene, one of the largest human genes, provides instructions for making a protein called parkin. Parkin plays a role in the cell machinery that breaks down (degrades) unwanted proteins by tagging damaged and excess proteins with molecules called ubiquitin. Ubiquitin serves as a signal to move unwanted proteins into specialized cell structures known as proteasomes, where the proteins are degraded. The ubiquitin-proteasome system acts as the cell's quality control system by disposing of damaged, misshapen, and excess proteins. This system also regulates the level of proteins involved in several critical cell activities such as the timing of cell division and growth. Because of its activity in the ubiquitin-proteasome system, parkin belongs to a protein group called E3 protein-ubiquitin ligases.

Studies of the structure and activity of parkin have led researchers to suggest other activities for this protein. Parkin may act as a tumor suppressor protein, which means it prevents cells from growing and dividing too rapidly or in an uncontrolled way. Parkin may also regulate the supply and release of sacs, called synaptic vesicles, from nerve cells. Synaptic vesicles contain chemical messengers that transmit signals from one nerve cell to another.

Parkinson disease - caused by mutations in the PARK2 gene

Researchers have identified more than 100 PARK2 mutations that cause juvenile Parkinson disease and some adult-onset cases. Some mutations lead to an abnormally small parkin protein, which is nonfunctional and degrades rapidly. Other mutations change the building blocks (amino acids) used to make parkin, and the altered protein cannot function properly. PARK2 mutations usually lead to a loss of parkin activity.

It is not clearly understood how PARK2 mutations cause Parkinson disease. The loss of parkin activity probably disturbs the ubiquitin-proteasome system, which allows unwanted proteins to accumulate. Accumulated proteins could disrupt normal cell activities such as the supply and release of synaptic vesicles, particularly those that contain a chemical messenger called dopamine. As parkin is normally abundant in the brain, its loss could lead to the impairment or death of nerve cells, including those that produce dopamine. Loss of dopamine-producing nerve cells is a characteristic feature of Parkinson disease.

cancers - associated with the PARK2 gene

The PARK2 gene spans part of a fragile area (known as FRA6E) on chromosome 6. This fragile area is unstable and prone to breakage and rearrangement. In tumors from some patients with ovarian or lung cancer, segments of the PARK2 gene within the FRA6E region are deleted or duplicated. As a result of these alterations, parkin activity is absent or reduced. These findings suggest that the PARK2 gene normally acts as a tumor suppressor gene, by restraining cell division and growth. If it is altered, cells can grow and divide in an uncontrolled manner, leading to a tumor.

other disorders - increased risk from variations of the PARK2 gene

Recent studies suggest that normal variations (polymorphisms) in the PARK2 gene (and a neighboring gene called PACRG) can increase the risk of contracting leprosy. Leprosy is a disease that affects the nerves and skin and is caused by the bacterium Mycobacterium leprae. It remains unclear how PARK2 polymorphisms increase leprosy susceptibility. Researchers believe that the ubiquitin-proteasome system may play a role in controlling infection. PARK2 polymorphisms may slightly alter parkin's function, making the ubiquitin-proteasome system less efficient.