Parkinson's disease (PD) is the most common motor system disorder and is caused by the loss of dopamine-producing neurons. Coding mutations have been identified in several PD-associated genes, yet it is often simply the over-expression of these genes that is implicated in the disease. The molecular mechanisms that cause aberrant expression of these genes are not well understood. Post-transcriptional regulation of mRNA stability and translation are increasingly acknowledged as key steps in gene expression control. Typically, control elements located in the 3' untranslated region (UTR) of mRNAs recruit microRNA (miRNA) complexes or regulatory proteins that influence mRNA decay and/or translation rates. One important family of 3' UTR regulatory proteins is the eukaryotic Puf family, which regulates diverse processes such as cell development, stem cell maintenance, neural function, and organelle biogenesis. At the molecular level, Puf proteins directly elicit translation initiation repression through protein interactions that inhibit cap-binding events, or stimulate deadenylation and decapping steps of decay through interactions with mRNA decay machinery. Recently, Puf proteins have also been found to act cooperatively with the miRNA regulatory system. With miRNAs known to be involved in many diseases, including Parkinson's, it is important to understand how Puf proteins coordinate with miRNAs to regulate target mRNAs in normal and disease conditions. Bioinformatic analyses revealed that many of the known PD-associated genes contain putative Puf binding sites in their 3' UTRs as well as potential miRNA binding sites. We hypothesize that Puf proteins and miRNAs normally work together to repress the PD mRNA targets in wild type cells, but the activity of Pufs or miRNAs may be compromised in the disease state, allowing upregulation of the targets.
The aims of this project will significantly advance the field of Parkinson's disease by revealing the extent to which Puf proteins are directly involved in coordinately regulating several mRNAs involved in PD.
The aims will also provide valuable information on the interplay between miRNA and Puf-mediated repression of these mRNAs. The knowledge gained from these studies will provide a new line of inquiry into Pufs as therapeutic targets for Parkinson's disease treatment. This grant will allow training of multiple PhD, Master's, undergraduate and high school students over a three-year period. Specifically, the grant will support two PhD students as well as 1-2 undergraduate assistants. In addition to the above students receiving financial support, the grant will provide training opportunities for 4-6 more Master's, undergraduate, and high school students.
This project will reveal novel mechanisms by which genes associated with Parkinson's disease are regulated at the level of mRNA stability and translation. By understanding the role of Puf proteins and miRNAs in regulating these genes, this project will provide a new avenue for therapeutic approaches to Parkinson's.
