This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We hypothesized that RDH12 protects photoreceptors from toxic medium-chain aldehydes produced during oxidative stress. If not cleared, these aldehydes lead to apoptosis. We investigated if RDH12 could detoxify 4-hydroxynonenal (4-HNE), one of the most toxic products of lipid peroxidation, released in cells during oxidative stress. We compared the toxicity of 4-HNE in presence and absence of RDH12, in vitro, in cultured cells, and in vivo. The toxicity of 4-HNE was measured by quantification of 4-HNE-protein adducts and cell death. In vitro and cell culture experiments were performed with exogenous 4-HNE. Wild-type and Rdh12 knockout mice were subjected to light to induce the release of endogenous 4-HNE in photoreceptors. RDH12 is protective against the formation of adducts in isolated retinal microsomes, cultured cells, and in retinas of mice subjected to dim cyclic light. Wild type RDH12 also significantly protects against 4-HNE-induced cell death in cultured cells. A mutation of RDH12 associated with Leber congenital amaurosis induces the loss of its protective function. RDH12 significantly protects mouse photoreceptors against bright light-induced cell death. The protective effect of RDH12 is due to reduction of 4-HNE to non-toxic alcohol, preventing adduct formation and apoptosis. Defective clearance of 4-HNE and other aldehydes could mediate the early onset vision loss and retinal dystrophy associated with mutations in RDH12 in patients with Leber congenital amaurosis. In this case, an adapted strategy for treatment would be to use molecules such as carcinine that have the ability to enter the cells and scavenge toxic aldehydes.
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