Weingarten, A. | bioRxiv Science

bioRxiv2026

Redox imbalance dictates dependence on GOT1 versus GOT2 for rod photoreceptor health during aging and stress

Photoreceptor (PR) loss causes vision loss in many blinding diseases, and effective therapies to prevent this cell loss are lacking. Aspartate aminotransferases (GOTs), located in the cytosol (GOT1) and mitochondria (GOT2), are key components of the malate-aspartate shuttle, which transfers reducing equivalents from cytosol to mitochondria. Previous work has implicated the GOTs as potential modulators of blinding retinal disease. To determine the roles of GOT1 and GOT2 in rod PRs, we generated rod PR-specific Got1 or Got2 conditional knockout mice (Got1 or Got2 cKO). We previously showed that Got1 cKO causes PR degeneration and is accompanied by NADH accumulation and a decreased retinal NAD+/NADH ratio. Here, we show that NADH oxidation via metabolic or genetic means prolongs PR survival in Got1 cKO animals, implicating NADH accumulation, or reductive stress, as a key driver of PR degeneration. In contrast, Got2 cKO causes minimal PR degeneration and alterations in retinal NADH and the NAD+/NADH ratio that oppose reductive stress. Interestingly, GOT2, but not GOT1, is decreased in multiple models of PR degeneration, including retinal detachment (RD) where the NAD+/NADH ratio favors a reductive state. Notably, loss of Got2 in PRs demonstrates a neuroprotective effect after experimental RD suggesting decreased GOT2 expression may be part of a stress response to promote PR survival. Overall, this study illustrates the differential dependence on the GOTs for PR health, provides evidence that an overly reductive environment is detrimental to PR survival, and identifies GOT2 as a novel therapeutic target with potentially broad application in blinding diseases.

neuroscience↗

bioRxiv2023

The absence of a neurogenic response to a repeated concussive-like injury in mice

In response to traumatic brain injury (TBI), the brain increases its generation of new neurons (neurogenesis) within the hippocampus, a brain region critical for learning and memory. Because neurogenesis plays important roles in learning and memory, post-traumatic neurogenesis may represent an adaptive response contributing to cognitive recovery. In contrast to increases in neurogenesis acutely after injury, levels of neurogenesis become impaired long after TBI. And although chronic deficits in neurogenesis after TBI have been reported by multiple groups, it is unknown whether the hippocampus remains capable of eliciting another neurogenic response to a repeated injury. To address this lack of knowledge, we used a closed head injury model that reflects a concussive-like injury or a mild TBI (mTBI) and assessed levels of neurogenesis in male and female adult mice. Mice received one or two mTBI or sham treatments 3 weeks apart. Compared to mice with a single mTBI, proliferation and neurogenesis were blunted in mice that received a second mTBI. This impaired response was unlikely due to a short recovery time between the two mTBIs as the proliferative response to a second mTBI was also impaired when two months were allowed between injuries. We further found that proliferation was impaired in the radial-glia like cells despite an intact pool. The mice that received two mTBIs also had a blunted intensity in their GFAP staining. In contrast to reports of aberrant post-TBI neurogenesis, we found that the neurons born after mTBI had normal dendritic branches. Lastly, we found that impairments in the inability to mount a neurogenic response after a second mTBI were associated with deficits in neurogenesisstrategy flexibility in the reversal water maze task. Our data suggests that a loss in the neurogenic response could in part contribute to worse cognitive recovery after a repeated concussion. These data may expose a novel target to help improve long-term cognitive outcome following repeated brain injury.

neuroscience↗