Some forms of familial Parkinson’s disease (PD) are due to mutations in the genes that code for the proteins PINK1, DJ-1 and parkin. These proteins have specific roles in the proper regulation of mitochondria, which are responsible for the majority of cellular energy production (ATP) in the cell. By studying pre-clinical models that have dysfunction in these PD genes, we will clarify their role and that of mitochondria in the disease process.
This project will characterize the changes in mitochondrial function and protein expression in PINK1, DJ-1 and parkin knockout models. First we will determine if, in fact, loss of these genes causes mitochondrial dysfunction. By using several well-characterized assays, we will assess the overall quality of the mitochondria and their ability to efficiently produce ATP. Second, we will examine the changes in mitochondrial protein levels (mitochondrial proteome) by mass-spectrometry based methods. Changes in protein levels will allow us to assess how the mitochondria are altered in each of these PD models. The mitochondrial proteome changes will also be entered into a database that will be freely accessible to other PD researchers.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Because the origin of sporadic and familial PD may both be intimately tied to mitochondrial function, characterization of specific changes in mitochondrial function or protein expression may focus our attention on possible routes of therapeutic intervention. In addition complete characterization of these models will further advance their utility as models for pre-clinical PD therapeutics.
This work will help to 1) define the pathophysiology underlying PD, 2) identify possible rational targets for future therapeutic intervention in PD, and 3) create a freely available database of proteomic changes in these important models. This work should be widely useful for the general characterization of mitochondrial dysfunction that may underlie PD and will further the utility of these PD models for other researchers.