Vacuolar ATPase subunit Atp6v0c transgene promotes neuroprotection and long-distance axon regeneration in injured retinal ganglion neurons.

Central nervous system (CNS) projection neurons' failure to repair or regenerate injured axons has devastating consequences for those who have sustained CNS injuries. Thus, there is a need for translatable factors capable of promoting long-distance axon regeneration in the CNS. We hypothesized that supporting lysosomes in injured neurons by supplementing their structural factors through gene therapy may foster axon regeneration. To test our hypothesis, we selected Atp6v0c for experimental regulation because it plays roles in lysosomal acidification and the degradation of misfolded proteins in response to endoplasmic reticulum (ER) stress in injured neurons. We tested this in a rodent optic nerve crush (ONC) model of traumatic optic neuropathy (TON), in which injured prototypical CNS projection neurons, the retinal ganglion cells (RGCs), do not regenerate damaged axons and eventually degenerate. Atp6v0c transgene expression was achieved using intravitreally injected adeno-associated virus serotype 2 (AAV2), which transduces the RGCs. For benchmarking, we compared efficacy to AAV2 targeting of prominent regulators of axon regeneration, Pten, and Klf9. We found that Atp6v0c transgene promoted RGC survival and long-distance axon regeneration, comparable to targeting Pten and Klf9. Thus, Atp6v0c is an axon regeneration-promoting factor with potential for treating CNS injury and disease.