Studying the impact of alpha-synuclein mutations on mitochondrial dynamics and synaptic function in neurons. . (360G-Wellcome-106713_Z_14_Z)

Dysfunction of alpha-synuclein protein is the critical event in the pathogenesis of Parkinson's disease and a full understanding of the mechanisms of synuclein-triggered pathology is required to develop new treatments for this devastating condition. Evidence from cell and animal models suggests that disease-causing mutations in alpha-synuclein principally lead to dysfunction in two key cellular compartments: mitochondrial and synaptic. However, whether compromised synaptic energy supply or calci um buffering due to impaired mitochondrial dynamics and function underpins neuronal and synaptic Parkinson's pathology remains unclear. In this project I will investigate the impact of alpha synuclein mutations on mitochondrial fission/fusion and trafficking dynamics in axons and presynaptic terminals, and the relationship of these to synaptic function. This will be investigated using state-of-the- art imaging approaches in primary neurons from rodent models of alpha- synuclein dysfunction and in human neurons, differentiated from established Parkinson's patient-derived induced pluripotent stem (iPS) cell lines. Abnormalities detected in this survey will be studied mechanistically at the molecular level. These abnormalities will also form the basis of high- throughput screens of modifiers of mitochondrial dynamics in human and rodent neurons with wildtype or mutated alpha-synuclein, in order to identify potential novel therapeutic targets for Parkinson's disease.