The Role of Nrf2 in SIRT1-Mediated RGC Neuroprotection in Traumatic Optic Neuropathy

Purpose: Traumatic optic neuropathy (TON), often occurring in traumatic brain injury (TBI) patients, is characterized by optic nerve damage, retinal ganglion cell (RGC) loss, and vision loss. Upregulation of sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, reduces RGC loss and vision deficits in TON models, but mechanisms underlying these effects are not well understood. This study examined if Nrf2, a transcription factor that regulates antioxidant enzymes, helps mediate neuroprotective effects of SIRT1 in TON. Methods: Wild-type (WT) and Nrf2-deficient mice received an intravitreal injection with adeno-associated virus type 2 (AAV2) expressing an RGC-selective promoter-driven human SIRT1, green fluorescent protein (GFP), or Nrf2. TON was induced by repetitive mild head impacts, and vision was assessed by optokinetic responses (OKRs). RGCs from isolated retinas were immunolabeled with Brn3a antibodies and counted to quantify Brn3a+ RGC numbers. Results: TON resulted in decreased Brn3a labeling and decreased OKR scores in AAV2/synuclein gamma (SNCG)/GFP-injected WT mice as compared with unimpacted mice; AAV2/SNCG/SIRT1 treatment attenuated this loss. This protective effect was absent in Nrf2-deficient mice subjected to TON, as these mice had significant decreases in Brn3a-labeled cells and OKR scores whether they received AAV2/SNCG/GFP or AAV2/SNCG/SIRT1 therapy. AAV2/SNCG/Nrf2-injected WT mice exhibited similar decreases in Brn3a labeling and OKR scores as AAV2/SNCG/GFP-injected WT mice. Conclusions: Nrf2 is implicated as an important downstream effector of SIRT1-mediated therapeutic effects given that Nrf2-deficient mice are unable to recapitulate the neuroprotective effects of AAV-based SIRT1 gene therapy. However, Nrf2 is not sufficient to induce similar neuroprotective effects when overexpressed selectively in RGCs. Translational Relevance: Results of this study define an important mechanism of SIRT1 gene therapy mediating RGC neuroprotection.