Abstract Retinal diseases (RDs) involve the degeneration of retinal cells, particularly retinal ganglion cells (RGCs), often driven by glutamate imbalance and aberrant signaling. We previously identified a presynaptic self-amplifying mechanism of glutamate overflow, where NMDA overstimulation activates JNK2-mediated phosphorylation of STX1A. To block this mechanism, a cell-permeable peptide, called JGRi1, was previously developed to disrupt the JNK2–STX1A interaction. Here, we investigated whether the inhibition of this pathway by JGRi1 could provide neuroprotection in retinal degeneration. We showed that JGRi1 efficiently reached the mouse retina upon topical administration as eye drops and granted retinal protection. Using an ex vivo optic nerve cut (evONC) model, we demonstrated that JGRi1 preserved RGC viability, reduced phosphorylation of JNK and STX1A, and lowered glutamate release. In retinal wholemounts, JGRi1 similarly preserved RGC survival. Furthermore, in an NMDA-induced degeneration model, JGRi1 protected RGCs, reduced glutamate levels, disrupted the JNK2–STX1A interaction, and limited microglial infiltration. Collectively, our findings highlight the central role of the JNK2–STX1A pathway in retinal degeneration and identify JGRi1 as a promising neuroprotective tool.
Cimino et al. (Wed,) studied this question.