This pilot proposal will expand on the recent finding that a dominant mutation in the retromer protein VPS35 causes Parkinson's disease (PD). Retromer proteins are involved in transport of proteins from the endosomes back to the trans-Golgi network. We propose to develop an in vitro model and to perform a series of analyses in order to identify the molecular mechanism(s) by which the mutant form of VPS35 causes PD. To create the model the PD mutant VPS35 protein will be expressed in a cell lines. Analysis will be performed on several levels. We will examine retromer function by analyzing receptor recycling in the cells expressing the PD mutant VPS35. Cells expressing the PD mutant VPS35 will be analyzed for biochemical changes such as changes in mitochondrial activity and protein secretion. Gene array analysis will be performed to identify potential changes in gene expression. The development of a novel in vitro model of PD will provide an opportunity to identify new molecular pathways and new avenues for therapeutic development.
This research has particular relevance to the VA patient care mission. The number of veterans over the age of 65 is now approximately 9.3 million (Veterans Health Administration Research Realignment Advisory Committee 1997). As our veteran population ages, these individuals and family members become increasingly susceptible to age-related diseases such as PD. The risk of developing PD increases 10 fold between the ages of 40 and 70 years to 1 in 100. Current pharmacological therapies do not halt the progression of PD. In an effort to fulfill the VA's mission to serve veterans, this research will provide information that can be utilized in the development of novel neuroprotective therapies to halt PD onset and progression.