Investigation of the synergistic role of PLK2 and alpha-synuclein in the regulation of neuronal homeostasis and functions

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Recent Progress: Alpha-synuclein (-syn) is a small soluble protein localized at presynaptic terminals in the central nervous system. Although this protein is abundantly expressed in the brain (1% of total cytosolic protein), its exact physiological functions remain unknown. In the past decade, there has been an increasing interest for the role of phosphorylation in the regulation of -syn normal function in vivo. In this context, our recent work identified Polo-like kinases (Plks) as the main kinases responsible for -syn phosphorylation in vitro and in vivo. Moreover, we reported that Plk2, a member of Plk family, regulates -syn selective clearance via the autophagy degradation pathway. However, the molecular mechanisms underlying Plk2-mediated -syn clearance and the exact synergistic physiological role of these two proteins remain unknown. Objective: The specific aims of the proposed research program are 1) to decipher the molecular mechanisms underlying -syn/Plk2 interaction and 2) to investigate the role of this pathway in the regulation of neuronal functions, with a focus in the control of the synaptic homeostasis. Methodology: This research program is based on a multidisciplinary approach combining histological and biochemical analysis, cell-based assays using mammalian cells and primary neuronal culture, as well as in vivo animal models. Impact: The 5-year deliverables of the proposed research program are 1) to identify new physiological functions of -syn and its natural kinase Plk2 and to shed light onto new molecular mechanisms underlying synaptic plasticity and homeostasis and 2) to train graduate students in molecular and cellular biology by developing a particular expertise in in vivo approaches.