Cell Autonomous Neuroprotection by the Mitochondrial Uncoupling Protein 2 in a Mouse Model of Glaucoma

Glaucoma is a group of disorders associated with retinal ganglion cell (RGC) degeneration and death. There is a clear contribution of mitochondrial dysfunction and oxidative stress toward glaucomatous RGC death. Mitochondrial uncoupling protein 2 (Ucp2) is a well-known regulator of oxidative stress that increases cell survival in acute models of oxidative damage. The impact of Ucp2 on cell survival during subacute and chronic neurodegenerative conditions, however, is not yet clear. Herein, we test the hypothesis that increased Ucp2 expression will improve RGC survival in a mouse model of glaucoma. We show that increasing RGC but not glial Ucp2 expression in transgenic animals decreases glaucomatous RGC death, but also that the PPAR-gamma agonist rosiglitazone (RSG), an endogenous transcriptional activator of Ucp2, does not significantly alter RGC loss during glaucoma. Together, these data support a model whereby increased Ucp2 expression mediates neuroprotection during a long-term oxidative stressor, but that transcriptional activation alone is insufficient to elicit a neuroprotective effect, motivating further research in to the post-transcriptional regulation of Ucp2.