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bioRxiv · 10.1101/2025.01.09.632264

OPTN protects retinal ganglion cells and ameliorates neuroinflammation in optic neuropathies

Wang, Q.·Wang, Y.·Jiang, Y. D. D.·Donahue, R.·Cao, G.·Yan, W.·Guo, H.·Hao, J.·Lu, Y.·Tian, F.
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Abstract

Optineurin (OPTN) is a crucial component of the homeostatic pathway, playing a pivotal role in regulating a number of essential signaling pathways including NF-{kappa}B, interferon, autophagy, and vesicular trafficking. The dysfunction of OPTN has been implicated in the pathogenesis of several diseases, such as primary open angle glaucoma (POAG), amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia, and Pagets disease of bone. Interestingly, mutations in OPTN are implicated as gain-of-function in glaucoma pathology and loss-of-function in ALS. However, the role of loss-of-function OPTN in glaucoma pathology remains unclear. Here, we demonstrate that OPTN dysfunction contributes to chronic neuroinflammation, leading to sustained RGC death, which may represent a shared pathological mechanism in both normal tension glaucoma (NTG) and high-tension glaucoma (HTG). Retinal conditioned OPTN knockout contributes to short-term astrogliosis and long-term microglia activation, with the propagation of microglia activation spreading to the optic nerve. Moreover, OPTN loss of function does not further exacerbate RGC death in the ocular hypertension mouse model induced by viscobead injection. Combined with the downregulation of OPTN in glaucoma patients, we have revealed an IOP-independent mechanism of glaucoma pathogenesis. Furthermore, we found that OPTN-driven NPY upregulation may suppress the CHOP-associated neurodegeneration. Our findings reveal a neuroprotective role for the OPTN-NPY signaling pathway, and its dysfunction promotes RGC loss in glaucoma pathology. The OPTN-NPY-mediated neuroinflammatory pathway provides a potential therapy for IOP-resistant glaucoma and highlights a druggable target for CHOP-associated neurodegeneration.

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Wang, Q., Wang, Y., Jiang, Y. D. D., Donahue, R., Cao, G., Yan, W., Guo, H., Hao, J., Lu, Y., Tian, F.. 2025-01-12. OPTN protects retinal ganglion cells and ameliorates neuroinflammation in optic neuropathies. https://doi.org/10.1101/2025.01.09.632264

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