NOTCH2NLC GGC repeat expansions cause retinal neurodegeneration in neuronal intranuclear inclusion disease mouse...

Neuronal intranuclear inclusion disease (NIID) patients frequently exhibit ocular abnormalities, yet the pathogenic mechanisms remain unclear. Using a transgenic mouse model ubiquitously expressing NOTCH2NLC with 98GGC repeats, we revealed that polyglycine aggregates, translated from the expanded GGC repeats, predominantly localize in PAX6- and RBPMS-positive cells, accompanied by retinal neurodegeneration and thinning especially in the inner retinal layers. Functional assessment through visual evoked potentials demonstrated significantly reduced amplitudes and prolonged latencies in NIID mice, indicating compromised visual pathway integrity. Transcriptomic profiling revealed dysregulation of glutathione redox homeostasis and antioxidant pathways in the NIID retina. We further demonstrated that GGC expansions induce mitochondrial abnormalities accompanied by glutathione depletion and accumulation of reactive oxygen species. Crucially, intravitreal administration of the mitochondrial-targeted antioxidant Mito-TEMPO significantly alleviated retinal damage and improved visual function. Our findings establish NOTCH2NLC GGC expansions as direct drivers of retinal pathology through mitochondrial-oxidative damage, while identifying antioxidant therapy as a promising treatment strategy for NIID-associated retinopathy.