Deciphering the role of calcineurin in the modulation of the growth cone proteins BASP-1 and GAP-43 at presynaptic terminals in response to alpha-synuclein toxicity

GAP-43 and BASP1 promote axonal branching upon neuronal injury due to their ability to regulate actin dynamics and vesicle recycling at presynaptic terminals, processes that are impaired in models of PD. We have shown that reducing calcineurin activity with low doses of the FDA-approved calcineurin inhibitor Tacrolimus, can prevent neurodegeneration in models of PD which was accompanied by an increase in the phosphorylation GAP-43 and BASP1. This proposal soughs to determine how calcineurin affects the function of GAP-43 and BASP1 to modulate axonal branching in a model of PD. Using primary dopaminergic and cortical cultures we will take a chemical and a genetic approach to modulate the calcineurin-dependent phospho-sites identified in GAP-43 and BASP1 and investigate these phospho-sites affect endocytosis, actin dynamics and electrical responses. These studies will reveal a mechanistic understanding on how calcineurin contributes to cell death in models of PD through the modulation of growth cone proteins.