Calcineurin-mediated regulation of GAP-43 is essential for neurite and synapse formation and protects against α-synuclein-induced degeneration
Rise in calcium (Ca2+) and hyperactivation of Ca2+-dependent phosphatase calcineurin are two key determinants of -synuclein (-syn) pathobiology implicated in synucleinopathies such as Dementia with Lewy Bodies and Parkinson's Disease. Calcineurin activity can be inhibited with FK506, a Food and Drug Administration (FDA)-approved compound. Our previous work demonstrated a protective effect of sub-saturating doses of FK506 against -syn pathology in a rat model of -syn neurodegeneration. This neuroprotection was associated with the phosphorylation of GAP-43. In this study, we present evidence that phosphorylation of GAP-43 regulated by calcineurin is a critical determinant for neurite branching and synapse formation. Phosphorylation of GAP-43 promotes neurite branching and synapse formation whereas dephosphorylation prevents it. Therefore, our findings provide a novel way in which GAP-43 activity can be regulated by calcineurin and provide the mechanistic basis for neuroprotection for FK506 effects in neurons experiencing -syn proteotoxic stress.