Aggregation of the protein alpha-synuclein and dysfunction of mitochondria (the powerhouse of the cell) are two critical components of Parkinson’s disease. We have recently found that the protein Pum2 can regulate alpha-synuclein protein synthesis at the vicinity of mitochondria. Interestingly, molecules called reactive oxygen species (ROS) made by mitochondria induce new protein synthesis from the alpha-synuclein mRNA pool associated with mitochondria. The proposed study will investigate Pum2-controlled newly generated alpha-synuclein protein and its effects on mitochondria.
We will test the hypothesis that alpha-synuclein translation is controlled by Pum2 in close vicinity of mitochondria and newly synthesized alpha-synuclein protein directly modulates mitochondrial functions. First, we will investigate if Pum2 is responsible for mitochondrial translocation of alpha-synuclein mRNA. Then, the role of Pum2 in mitochondrial ROS-mediated alpha-synuclein protein synthesis will be further tested. Next, we will examine the direct role of newly synthesized alpha-synuclein in mitochondrial respiratory functions.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Alpha-synuclein is considered as a major pathological component in Parkinson’s disease, and thereby a key therapeutic target. However, only a handful of studies address the molecular mechanisms governing expression control of alpha-synuclein. Our study will bring new insight into our understanding of translational control of alpha-synuclein and may open new avenues for developing new treatment for Parkinson’s disease.
We expect to understand a Pum2-mediated mechanism that controls alpha-synuclein protein synthesis near mitochondria. We also expect to observe that mitochondrial ROS cause new alpha-synuclein protein synthesis from mitochondria-associated mRNA and this new population of alpha-synuclein in turn modulates mitochondrial functions.
Alpha-synuclein is a major pathogenic molecule that is found in Lewy bodies, pathological hallmark, in Parkinson’s disease patient brain. During the funding period, we have investigated the Role of Pum2, RNA binding protein, in regulation of alpha-synuclein protein synthesis near mitochondria. We found that alpha-synuclein mRNA is localized to mitochondria and new protein synthesis is repressed by Pum2 until mitochondrial reactive oxygen species (ROS) are released. Upon triggered by mitochondrial ROS, alpha-synuclein protein is newly synthesized near mitochondria and modifies mitochondrial functions.