Mutations in the parkin gene play a prominent role in Parkinson's disease as mutations in parkin are the main genetic cause of autosomal recessive Parkinson's disease and mutations in parkin also appear to play a role in familial Parkinson's disease. Parkin plays a pivotal role in the ubiquitin proteasomal pathway (UPP) by functioning as an ubiquitin E3 ligase. Most disease causing mutations of parkin are thought to be loss of function mutations that ultimately lead to the absence of ubiquitination and the subsequent failure of UPP-mediated degradation of parkin substrates. Thus, the abnormal accumulation of parkin substrates could play a role in the demise of substantia nigra dopaminergic neurons in patients with parkin mutations.
Moreover, inactivation of parkin through dopaminergic and oxidative and nitrosative stress may play a role in sporadic Parkinson's disease. The stress activated non-receptor tyrosine kinase c-Abl phosphorylates and inactivates parkin and may play a critical role in sporadic Parkinson's disease by inactivating parkin.
Project 1 proposes to characterize the role of c-Abl mediated inactivation of parkin and its relationship to oxidative and nitrosative stress in sporadic Parkinson's disease as well as the role of parkin substrates in the pathogenesis of Parkinson's disease. In specific Aim 1 they will evaluate characterize c-Abl phosphorylation of parkin. In specific Aim 2 they will evaluate and characterize the role of oxidative and nitrosative stress mediated inactivation of parkin. In specific Aim 3 in collaboration with Project 2 they will evaluate and characterize the role of c-Abl in PD and in an animal model of a-synucleinopathy. In specific aim 4 with Core B, Core C, and Core D they will characterize the role of AIMP2 in the pathogenesis of Parkinson's disease due to inactivation of Parkin.
Understanding the function and role of c-Abl and oxidative/nitrosative stress mediated inactivation of parkin may provide novel therapeutics targets to prevent the toxic effects of parkin deficiency in the degenerative process of Parkinson's disease.