Isolating region specific α-syn-mediated mechanisms in mitochondrial function in vivo

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Parkinson's disease (PD) is characterized by the loss of dopaminergic (DA) neurons and the accumulation of Lewy Bodies (LB), but the underlying causative mechanism is unknown. So far, mutations in more than 8 genes, implicated in many different cellular pathways are identified to cause familial PD (fPD). However, these genes are also risk factors for sporadic PD (sPD), suggesting that both fPD and sPD could arise due to common patho- logical mechanisms. Interestingly, while a plethora of mitochondrial processes are thought to be influenced by mutant α-syn, the protein that is present in Lewy Bodies, fundamental questions still remain as to how normal, unmutated α-syn contributes to mitochondrial homeostasis and how mutant, diseased α-syn cause mitochon- drial dysfunction seen in PD. This is because several reports show contrasting/conflicting results depending on the cell types used and the α-syn expression level tested. Therefore, to address this gap in knowledge what is currently lacking is a cohesive strategy to successfully unravel the physiological from the pathological role of α- syn in mitochondrial biology in vivo. The long-term goal of this proposal is to understand how α-syn-mediated mitochondrial dysfunction contributes to PD at the resolution of a single mitochondrion in a whole organism. The central hypothesis of this proposal is that particular regions of α-syn have critical roles in maintaining mi- tochondrial homeostasis. Using transgenic animals containing N-terminal deletions or C-terminal PTM dele- tions, two predictions will be tested: 1) the N-terminus of α-syn affects mitochondrial fragmentation pathways, and 2) the C-terminus of α-syn affects mitochondrial damage/oxidation mechanisms. A unique strategy that utilizes in vivo imaging and computation analysis of signal mitochondrion in a genetic model organism (Dro- sophila) coupled with biochemistry will be employed. The rational is that once the a-syn-mediated roles on mi- tochondrial biology are uncovered, innovative approaches to target effective therapeutics to maintain mitochon- drial health can be initiated. Currently there are no cures for PD. Current FDA approved treatments only reduce symptoms. This work has significant impact on isolating the region specific α-syn-mediated mechanisms on mitochondrial biology, and obtaining knowledge on how a common pathway contributes to PD pathology, em- phasizing a novel avenue for targeted therapeutics early before neuronal loss and clinical manifestation of both fPD/sPD. This work is innovative as it represents a new/substantive departure from the status quo; the ap- proach of isolating the physiological and pathological roles of a-syn in mitochondrial health in vivo, in an organ- ism; highlighting a potential disease pathway for the clinical manifestation of not just PD, but also other synu- cleinopathies, including stress induced TBI. The proposed research is significant, because it is expected to verti- cally advance/expand current knowledge on how PD is initiated, considerably impacting current paradigms to dramatically propel the development of novel modifiers against a-syn-mediated mitochondrial defects.