Parkinson's disease is a complex neurodegenerative disorder that is both sporadic and familial. It is currently thought that Parkinson's disease results from a combination of environmental factors and genetic susceptibility. Gene mutations in the leucine-rich repeat kinase 2 (LRRK2) have recently been shown to result in autosomal dominant Parkinson's disease.
A high prevalence of these mutations in unrelated Parkinson's disease patients strongly suggests that mutant LRRK2 may play a key role in sporadic Parkinson's disease as well. The clinical and pathological phenotypes of LRRK2 Parkinson's disease patients are similar to classic late-onset Parkinson's disease, further emphasizing the potential importance of this gene. Biochemical evidence suggests that aberrant GTPase and kinase activities are linked to disease causing mutations, and may be at the basis of neuronal toxicity and pathogenesis of Parkinson's disease.
The cell biology and pathobiological actions of LRRK2 are not yet known. To understand the role of LRRK2 in the function and dysfunction of neurons, Project 3 has generated LRRK2 knockout mice and LRRK2 transgenic mice.
In specific Aim 2, they will explore the effects of oxidative stress in genetically engineered LRRK2 mice to examine the interplay of genetics and environmental effects on neuropathology.
Since increased activity of LRRK2 is associated with neurotoxicity they will explore in collaboration with Project 2, in specific Aim 3 they will examine the cellular regulation of LRRK2 expression by the E3 ubiquitin ligase CHIP and its effect on neuronal viability. They expect that LRRK2 functions in large protein complexes and thus propose in specific Aim 4 to identify and characterize LRRK2 interacting proteins.
The long-term goals of this project are to identify and characterize the interaction of LRRK2 and its protein targets with the hope that these studies of LRRK2 may potentially lead to the development of new medication to treat Parkinson's disease.