LRRK2 and Parkinson's Disease
On Thursday, September 17, 2008, news media around the world reported on the role of a mutation in the gene LRRK2 in Parkinson's disease. The reports were prompted by the revelation by Google co-founder Sergey Brin that he and his mother, who lives with PD, both are carriers of the mutation.
To help patients interpret the news and its potential relevance to their own PD and treatment, The Michael J. Fox Foundation's Research team has assembled answers to fundamental questions on the field's current understanding of LRRK2 and its role in PD.
How much do we know today about the role of genetics in causing PD?
The exact role of genetics in PD is still being investigated. Genetic, or familial, cases of Parkinson's disease make up a small minority of all PD cases -- an estimated five to 10 percent. But advances from genetic studies hold potential to open new avenues toward the development of therapeutics that will benefit all PD patients, including those living with the far more common sporadic form of PD.
What is the specific implication of LRRK2 in PD?
In 2004, several independent groups first reported the link between mutations in the gene LRRK2 (leucine-rich repeat kinase 2) gene and PD in a number of families with a history of PD. Today it is believed that mutations in LRRK2 may be the most common genetic form of PD.
Studies suggest that mutations in the LRRK2 gene are present worldwide in about one percent of sporadic PD and about four percent of familial PD. However, when limited to certain ethnic groups, this frequency is much higher. For example, in Ashkenazi Jews, about 10 percent of sporadic and 28 percent of familial cases with LRRK2 mutations have been reported, while in North African Arabs, the frequency in both sporadic and familial cases is between 35 to 40 percent.
The LRRK2 gene codes for a protein, LRRK2 (also known as dardarin), whose function in the cell is not yet known; however, it shares structural and functional similarities with other important cell enzymes called kinases, which are important for activating/inactivating other proteins. At least some mutations appear to cause the LRRK2 protein to become overactive, and this can lead to death of cells. However, a direct link between this enhanced enzymatic activity and cell death in human or animal models of PD has yet to be definitively shown.
The news media are reporting on a specific LRRK2 mutation, G2019S. Is this the only known mutation associated with PD?
No. In fact, there are as many as 37 known LRRK2 mutations, but genetic evidence of pathogenicity has been shown for only about five. The mutation G2019S is one of these five and is the subject of active and aggressive research funded by MJFF and others.
In his blog, Sergey Brin states that his risk of developing PD lies somewhere between 20 percent