Cuproptosis-associated retinal degeneration in a mouse model of retinitis pigmentosa and neuroprotection by copper chelation.

Cuproptosis is a recently described copper-dependent form of regulated cell death linked to mitochondrial metabolism, but its relevance to retinal degeneration in retinitis pigmentosa is unknown. Here, we investigated whether cuproptosis-associated changes occur in the retina of the rd10 mouse model of retinitis pigmentosa and whether copper chelation confers neuroprotection. Cuproptosis-associated changes were assessed by measuring retinal copper accumulation, dihydrolipoamide S-acetyltransferase oligomerization, and iron-sulfur cluster protein expression. The copper chelator D-penicillamine was delivered by intravitreal injection, and treatment effects were evaluated using retinal histology, electroretinography, and visually guided behavioral assays. Degenerating rd10 retinas exhibited increased copper accumulation, enhanced dihydrolipoamide S-acetyltransferase oligomerization, and reduced iron-sulfur cluster-associated proteins, consistent with activation of cuproptosis-associated pathways. D-penicillamine attenuated these molecular changes, improved mitochondrial protein markers, and significantly preserved photoreceptor structure. Functional benefit was detectable in light perception behavior, although electroretinographic and optomotor responses were not significantly restored. The copper exporter ATPase copper transporting β was upregulated at an early stage but reduced during peak degeneration, whereas the copper importer copper transporter 1 increased at the later stage, suggesting dynamic copper dyshomeostasis. These findings identify cuproptosis-associated molecular changes as a feature of photoreceptor degeneration in rd10 mice and demonstrate that copper chelation provides structural neuroprotection.