Parkinson disease susceptibility gene mutations in Drosophila melanogaster and the therapeutic potential of transgenes alternative oxidase and alternative NADH dehydrogenase
Start date: Aug 1, 2011,
End date: Jan 31, 2014
Mutations in human genes parkin and DJ-1 cause susceptibility to Parkinson's disease (PD). Both genes have functions linking them to mitochondria and oxidative stress. Parkin protein is a ubiqutin E3 ligase which targets damaged proteins for proteasomal degradation and it has also been shown to localize to dysfunctional mitochondria. Protein DJ-1 has functions as a ROS scavenger and a gene expression regulator of other stress genes. My research uses Drosophila melanogaster lines with mutations in the genes parkin and DJ-1β, which are homologous to the human PD susceptibility genes. These mutant lines have characterized phenotypes displaying both locomotory defect and decreased resistance to oxidative stress. The alternative oxidase (AOX) is a gene commonly found in many plants and fungi but absent in most animals, it provides a by-pass to mitochondrial complexes III and IV. The alternative NADH dehydrogenase (NDI1) is a Saccaromyces Cerevisiae enzyme that provides by-pass the mitodhoncrial complex I. We have seen that the expression of AOX and NDI1, also at high levels, is well tolerated by the Drosophila melanogaster . We also have data demonstrating that the AOX and NDI1 proteins localize to mitochondria and that they provide resistance againts ETC inhibitors, thus making them mitochondrial antioxidants. The aim of the proposed research project is to study the pathogenesis of DJ-1β and parkin mutations in Drosophila. For this purpose I will be using in vivo fly models and primary neuron cultures isolated from the mutant and/or transgenic flies. The mitochondrial and cytosolic reactive oxygen species ( ROS) levels increased by low levels of ETC inhibitors, and my endeavor is to examine how the increased ROS levels affect the pathogenesis of parkin and DJ-1β mutations. and is there therapeutic potential in the transgenic expression of mitochondrial antioxidants.
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