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.

Mitochondrial Protection by Exogenous Otx2 in Mouse Retinal Neurons.

OTX2 (orthodenticle homeobox 2) haplodeficiency causes diverse defects in mammalian visual systems ranging from retinal dysfunction to anophthalmia. We find that the retinal dystrophy of Otx2(+/GFP) heterozygous knockin mice is mainly due to the loss of bipolar cells and consequent deficits in retinal activity. Among bipolar cell types, OFF-cone bipolar subsets, which lack autonomous Otx2 gene expression but receive Otx2 proteins from photoreceptors, degenerate most rapidly in Otx2(+/GFP) mouse retinas, suggesting a neuroprotective effect of the imported Otx2 protein. In support of this hypothesis, retinal dystrophy in Otx2(+/GFP) mice is prevented by intraocular injection of Otx2 protein, which localizes to the mitochondria of bipolar cells and facilitates ATP synthesis as a part of mitochondrial ATP synthase complex. Taken together, our findings demonstrate a mitochondrial function for Otx2 and suggest a potential therapeutic application of OTX2 protein delivery in human retinal dystrophy.

Otx2 promotes the survival of damaged adult retinal ganglion cells and protects against excitotoxic loss of visual acuity in vivo.

Retinal ganglion cells (RGCs) are the projection neurons from the eye to the brain and their loss results in visual impairment in a number of diseases. Transcription factors with a homeodomain can translocate between cells and, in at least one reported case, can stimulate neuronal survival. Otx2 is a homeoprotein transcription factor expressed in the retina that is taken up by RGCs. We thus hypothesized that Otx2 capture could regulate the survival of adult RGCs. We report that Otx2 stimulates the survival of adult mouse and rat RGCs in vitro and protects RGCs against NMDA-induced toxicity in vivo in mice. In the latter model, Otx2 also preserves visual acuity.