Pum2-dependent translational regulation of a-SYN near mitochondria and contribution to the pathogenesis of Parkinson's disease

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Alpha-synuclein (α-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 α-SYN toxicity seems to affect mitochondria most significantly. Complex interplay between α-SYN and mitochondria has been widely observed. While the intricate crosstalk between mitochondria and α-SYN is poorly understood, our preliminary studies suggest that the 3'-untranslated region (3'-UTR) of α-SYN mRNA plays a key role in translational regulation of α-SYN near mitochondria. Our preliminary findings demonstrate that 1) α-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 α-SYN transcript; 3) interestingly, mitochondrial Pum2 levels in post-mortem PD brain were significantly lower compared to control subjects, while α-SYN levels were opposite, implying Pum2’s repressive role on α-SYN near mitochondria. In addition, recent studies showing the association of single nucleotide polymorphisms in the α-SYN 3'-UTR with PD strongly suggest that 3`-UTR-mediated regulation of α-SYN could become a critical player in PD pathogenesis. Our central hypothesis is that deregulation of Pum2-mediated α-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 α-SYN will be identified. In Aim 2, it will be determined how mitochondrial ROS controls Pum2-mediated translation of α-SYN mRNA and the roles of newly synthesized α- SYN. In Aim 3, it will be investigated whether PD-associated SNPs in the 3'-UTR of α-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 α-SYN expression near mitochondria in PD pathogenesis by elucidating the role of Pum2 and the 3'-UTR of α-SYN in translational regulation