Tailoring UPS-to-autophagy transition to restore RGC prosperity and functionality in a rodent traumatic optic neuropathy model.

Direct or indirect injury to the optic nerve can lead to traumatic optic neuropathy (TON), a pathological process eventually resulting in long-term vision loss. Experimentally, optic nerve crush (ONC) simulates TON by inducing retinal ganglion cell (RGC) apoptosis and vision loss. This study investigates the neuroprotective effect of a HECT domain-E3 ubiquitin ligase inhibitor, Compound 056, on retinal ganglion cells after traumatic injury. Experimental traumatic optic neuropathy (TON) was induced by mechanical compression of the rodent optic nerve. Compound 056 was administered (60 mg/kg) subcutaneously once on the same day after TON induction. Compound 056 treatment (60 mg/kg) significantly increased RGC survival and preserved visual function after TON induction. The number of TUNEL-positive cells was significantly decreased, and optic disc edema was reduced. Bulk RNA sequencing revealed that HUWE1, an E3 ubiquitin ligase, was potentially linked to the suspended autophagy and NLRP3-mediated neuroinflammation after TON induction. We demonstrated that compound 056 effectively alleviated neuroinflammation and enhanced autophagic flux at transcriptomic and protein levels. These findings suggest compound 056 may have therapeutic potential in treating TON by modulating NLRP3 inflammasome pathways and the autophagic flux within the retina and optic nerve.