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bioRxiv · 10.1101/2024.09.18.613712

Ocular hypertension impairs axonal transport in the optic nerve head leading to neurodegeneration in a novel Cre-inducible mouse model of myocilin glaucoma.

Kaipa, B. R.·Kasetti, R.·Li, L.·Millar, C.·Cho, W.·Skowronska-Krawczyk, D.·Maddineni, P.·Sundaresan, Y.·zode, g.
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Abstract

Elevation of intraocular pressure (IOP) due to trabecular meshwork (TM) dysfunction, leading to neurodegeneration, is the pathological hallmark of primary open-angle glaucoma (POAG). Impaired axonal transport is an early and critical feature of glaucomatous neurodegeneration. However, a robust mouse model that replicates these human POAG features accurately has been lacking. We report the development and characterization of a novel Cre-inducible mouse model expressing a DsRed-tagged Y437H mutant of human myocilin (Tg.CreMYOCY437H). A single intravitreal injection of HAd5-Cre induced selective MYOC expression in the TM, causing TM dysfunction, reducing outflow facility, and progressively elevating IOP in Tg.CreMYOCY437H mice. Sustained IOP elevation resulted in significant retinal ganglion cell (RGC) loss and progressive axonal degeneration in Cre-induced Tg.CreMYOCY437H mice. Notably, impaired anterograde axonal transport was observed at the optic nerve head before RGC degeneration, independent of age, indicating that impaired axonal transport contributes to RGC degeneration in Tg.CreMYOCY437H mice. In contrast, axonal transport remained intact in ocular hypertensive mice injected with microbeads, despite significant RGC loss. Our findings indicate that Cre-inducible Tg.CreMYOCY437Hmice replicate all glaucoma phenotypes, providing an ideal model for studying early events of TM dysfunction and neuronal loss in POAG.

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Kaipa, B. R., Kasetti, R., Li, L., Millar, C., Cho, W., Skowronska-Krawczyk, D., Maddineni, P., Sundaresan, Y., zode, g.. 2024-09-19. Ocular hypertension impairs axonal transport in the optic nerve head leading to neurodegeneration in a novel Cre-inducible mouse model of myocilin glaucoma.. https://doi.org/10.1101/2024.09.18.613712

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