Exogenous Otx2 protects midbrain dopaminergic neurons from MPP+ by interacting with ATP5a1 and promoting ATP synthesis

Mitochondrial dysfunction is the main pathological mechanism responsible for the death of midbrain dopaminergic (mDA) neurons. Thus, mitochondria-targeting therapy is a potential therapeutic strategy for Parkinson's disease (PD). Homeodomain transcription factors such as Otx2 can translocate between cells and exert non-cellular autonomous functions in recipient cells to stimulate neuronal survival. In this study, we investigated if exogenous Otx2 acts as a survival factor for mDA neurons by protecting them against MPP+-induced neurotoxicity in vitro. We show that subacute MPTP dosing regimen induces significant reduction in the levels of Otx2 homeoprotein in the ventral midbrain of PD mice. We also show that exogenous Otx2-myc recombinant protein protected primary mDA neurons against MPP+ by interacting with ATP5a1and promoting ATP synthesis.