Project Summary/Abstract
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.