Identifying the effects of mutations in the Rab domain on Leucine-Rich Repeat Kinase 2 (LRRK2) function

Parkinson's Disease (PD) is the second most common neurodegenerative disorder in the Western World. Although the majority of cases occur sporadically, several genes have been identified, that, when mutated, lead to familial PD. Of these genetic loci, the Park8 gene encoding a complex, multi-domain protein known as the Leucine-Rich Repeat Kinase 2 (LRRK2), has raised particular interest because of its Roc (Rab) domain. Rab proteins are small GTPases that act as molecular switches in the cell through the cycling of GTP (active) and GDP (inactive). The Rab domain of LRRK2 previously was shown to bind GTP, and so the effects of mutations in this domain were studied in the cell model. It was found that mutations in the Rab domain had a slower rate of GTP hydrolysis when compared to the wild-type, and that an overexpression of these mutations led to neuronal cell death. One mutation in particular had an unusual phenotypic expression in the cell model as well. LRRK2 was previously shown to have kinase activity. Therefore, if the Rab domain within LRRK2 regulates the kinase domain of the protein through GTP hydrolysis, mutations within the Rab domain could make it constitutively active, thereby increasing LRRK2's kinase activity resulting in an unusual cell phenotype that could eventually result in neuronal cell death