Role of PINK1 and parkin in the pathogenesis of Parkinson's disease

As a new post-doctoral fellow, I submit this two-year project to seek support to train in the molecular biology of Parkinson’s disease (PD), a common neurodegenerative disorder of unknown cause. Clinically, PD is characterized by tremor, stiffness, slowness of movements and postural instability primarily due to the loss of dopaminergic neurons in the substantia nigra of the midbrain. In some patients, the disease is inherited due to mutations in PARK genes. PARK2 and PARK6 encode for parkin and PINK1, respectively, two proteins shown to be implicated in the regulation of mitochondrial morphology and dynamics. To acquire a deeper understanding of the physiological function of these proteins, and ultimately of the neurobiology of PD, I propose the following project. First, I will systematically compare the consequences of a lack of PINK1 and/or parkin on mitochondrial dynamics in subpopulation of cultured primary neurons known to be severely and minimally affected in PD. Second, I will determine whether these changes are associated to functional perturbations of mitochondria and neurons.