Several genes have now been definitively linked to PD. The first to be identified was alpha-synuclein. In the 1990s, researchers at NIH and other institutions studied the genetic profiles of a large Italian family and three Greek families with familial PD and found that their disease was related to a mutation in this gene. They found a second alpha-synuclein mutation in a German family with PD. These findings prompted studies of the role of alpha-synuclein in PD, which led to the discovery that Lewy bodies from people with the sporadic form of PD contained clumps of alpha-synuclein protein. This discovery revealed a potential link between hereditary and sporadic forms of the disease.
In 2003, researchers studying inherited PD discovered that the disease in one large family was caused by a triplication of the normal alpha-synuclein gene on one copy of chromosome 4. This triplication caused people in the affected family to produce too much of the normal alpha-synuclein. This study showed that an excess of the normal form of the protein could result in PD, just as the abnormal form does.
Other genes linked to PD include parkin, DJ-1, PINK1, and LRRK2. Parkin, DJ-1, and PINK-1 cause rare, early-onset forms of PD. The parkin gene is translated into a protein that normally helps cells break down and recycle proteins. DJ-1 normally helps regulate gene activity and protect cells from oxidative stress. PINK1 codes for a protein active in mitochondria. Mutations in this gene appear to increase susceptibility to cellular stress.
LRRK2, which is translated into a protein called dardarin, was originally identified in several English and Basque families and causes a late-onset form of PD. Subsequent studies have identified this gene in other families with PD as well as in a small percentage of people with apparently sporadic PD.
Researchers are continuing to investigate the normal functions and interactions of these genes in order to find clues about how PD develops. They also have identified a number of other genes and chromosome regions that may play a role in PD, but the nature of these links is not yet clear.