Alpha-synuclein (?-SYN) and mitochondrial dysfunction are two central components in Parkinson's disease (PD) pathogenesis. Mitochondrial dysfunction is a common feature of the many iterations of PD pathogenesis and ?-SYN toxicity seems to affect mitochondria most significantly. Complex interplay between ?-SYN and mitochondria has been widely observed. While the intricate crosstalk between mitochondria and ?-SYN is poorly understood, our preliminary studies suggest that the 3'-untranslated region (3'-UTR) of ?-SYN mRNA plays a key role in translational regulation of ?-SYN near mitochondria. Our preliminary findings demonstrate that 1) ?-SYN mRNA is localized to the mitochondrial surface where its translation is initiated by mitochondrial ROS; 2) this translational control is governed by Pum2, a RNA-binding translational repressor, which binds to the 3'-untranslated region (3'-UTR) of ?-SYN transcript; 3) interestingly, mitochondrial Pum2 levels in post-mortem PD brain were significantly lower compared to control subjects, while ?-SYN levels were opposite, implying Pum2?s repressive role on ?-SYN near mitochondria. In addition, recent studies showing the association of single nucleotide polymorphisms in the ?-SYN 3'-UTR with PD strongly suggest that 3`-UTR-mediated regulation of ?-SYN could become a critical player in PD pathogenesis. Our central hypothesis is that deregulation of Pum2-mediated ?-SYN translational repression on the outer surface of mitochondria contributes to mitochondrial dysfunction observed in PD. The following three specific aims will be pursued:
In Aim 1, both the cis-regulatory elements and the trans- factors responsible for mitochondrial localization of ?-SYN will be identified.
In Aim 2, it will be determined how mitochondrial ROS controls Pum2-mediated translation of ?-SYN mRNA and the roles of newly synthesized ?- SYN.
In Aim 3, it will be investigated whether PD-associated SNPs in the 3'-UTR of ?-SYN cause changes in Pum2 binding, translocation of the protein to mitochondria, and mitochondrial functions. The successful completion of this project could create a paradigm shift in our understanding of molecular mechanisms that control ?-SYN expression near mitochondria in PD pathogenesis by elucidating the role of Pum2 and the 3'-UTR of ?-SYN in translational regulation
The proposed research is relevant to public health because determining the role of the ?-synuclein (?-SYN) mRNA 3'UTR and mitochondrial involvement in expression control of ?-SYN are expected to facilitate the understanding of Parkinson's disease (PD) pathogenesis and development of new therapies to improve the quality of life of people with PD. Therefore, the proposed study is closely relevant to the mission of NIH and NINDS.