LRRK2

The LRRK2 gene provides instructions for making a protein called dardarin. The LRRK2 gene is active in the brain and other tissues throughout the body, but little is known about this gene or the dardarin protein.

Studies of the gene's instructions have revealed some clues about dardarin's function. Part of the LRRK2 gene provides instructions for making a protein segment that is rich in a protein building block (an amino acid) called leucine. Proteins with leucine-rich regions appear to play a role in activities that require protein-protein interactions, such as transmitting signals or helping to assemble the cell's structural framework (cytoskeleton). Other parts of the LRRK2 gene provide instructions for protein regions called the ROC-COR domain and the WD40 domain. These domains also suggest that dardarin is capable of multiple protein-protein interactions.

Additional research findings indicate that dardarin has an enzyme activity known as kinase. Proteins with kinase activity assist in the transfer of a phosphate group (a cluster of oxygen and phosphate atoms) from the energy molecule ATP to amino acids in certain proteins. This phosphate transfer is called phosphorylation, and it is an essential step in turning on and off many cell activities. Dardarin may have a second enzyme activity referred to as a GTPase activity. This activity is associated with a region of the protein called the ROC domain. The ROC domain may act as a molecular switch that controls the overall shape of the dardarin protein.

Parkinson disease - caused by mutations in the LRRK2 gene

Researchers have identified at least 20 LRRK2 mutations in families with late-onset Parkinson disease. These mutations replace one amino acid with another amino acid in the dardarin protein, which affects the protein's structure and function. It is unclear how LRRK2 mutations lead to Parkinson disease.

A mutation that replaces the amino acid arginine with the amino acid glycine at protein position 1396 (written as Arg1396Gly or R1396G) is a relatively common cause of Parkinson disease in the Basque region between France and Spain. The protein name dardarin comes from the Basque word dardara, which means tremor, a characteristic feature of Parkinson disease.

Studies of several different populations from around the world revealed a common LRRK2 mutation that is found in 3 to 7 percent of familial Parkinson disease cases. This mutation replaces the amino acid glycine with the amino acid serine at protein position 2019 (written as Gly2019Ser or G2019S). The incidence of the Gly2019Ser mutation in familial cases is highest among Arabs from North Africa and people of Ashkenazi (eastern and central European) Jewish ancestry, and it is lowest in Asian and northern European populations. This particular mutation has also been reported in 1 to 3 percent of sporadic Parkinson disease cases, in which there is no family history of the disease.

Studies in Chinese and Japanese populations have identified an LRRK2 mutation that occurs more frequently in people with Parkinson disease than in people without the disease. This mutation replaces the amino acid glycine with the amino acid arginine at protein position 2385 (written as Gly2385Arg or G2385R). This mutation appears to increase the risk of Parkinson disease among people in these populations.