Abstract
Glaucoma is a leading cause of irreversible vision loss due to retinal ganglion cell (RGC) degeneration that develops slowly with age. Elevated intraocular pressure (IOP) is a significant risk factor, although many patients develop glaucoma with IOP in the normal range. Mutations in microfibril-associated genes cause glaucoma in animal models, suggesting the hypothesis that microfibril defects contribute to glaucoma. To test this hypothesis, we investigated IOP and functional/structural correlates of RGC degeneration in mice of either sex with abnormal microfibrils due to heterozygous Tsk mutation of the fibrilin-1 gene (Fbn1Tsk /+). Although IOP was not affected, Fbn1Tsk /+ mice developed functional deficits at advanced age consistent with glaucoma, including reduced RGC responses in electroretinogram (ERG) experiments. While RGC density in the retina was not affected, the density of RGC axons in the optic nerve was significantly reduced in Fbn1Tsk /+ mice. However, reduced axon density correlated with expanded optic nerves, resulting in similar numbers of axons in Fbn1Tsk /+ and control nerves. Axons in the optic nerves of Fbn1Tsk /+ mice were significantly enlarged and axon diameter was strongly correlated with optic nerve area, as has been reported in early pathogenesis of the DBA/2J mouse model of glaucoma. Our results suggest that microfibril abnormalities can lead to phenotypes found in early-stage glaucomatous neurodegeneration. Thinning of the elastic fiber-rich pia mater was found in Fbn1Tsk /+ mice, suggesting mechanisms allowing for optic nerve expansion and a possible biomechanical contribution to determination of axon caliber.
Highlights
Glaucoma, a leading cause of irreversible vision loss and blindness, is a neurodegenerative disease associated with aging defined by a specific pattern of optic nerve damage and visual field loss (Davis et al, 2016; Jonas et al, 2017)
A trend toward decreasing intraocular pressure (IOP) with advancing age was apparent in both lines of mice, which was statistically significant for wt, but not significant for Fbn1Tsk/ϩ mice
To determine whether tonometer calibration was affected by cornea thickness, we measured IOP in eyes of Fbn1Tsk/ϩ and wt mice with IOP fixed at various pressures by variable-height reservoir
Summary
A leading cause of irreversible vision loss and blindness, is a neurodegenerative disease associated with aging defined by a specific pattern of optic nerve damage and visual field loss (Davis et al, 2016; Jonas et al, 2017). A leading hypothesis of glaucoma is that. Received July 3, 2018; accepted October 13, 2018; First published October 23, 2018. The authors declare no competing financial interests. September/October 2018, 5(5) e0260-18.2018 1–18 deficits in axon transport, likely resulting from mechanical stress at the optic nerve head, initiate slowly developing axon degeneration and eventual death of retinal ganglion cells (RGCs; Calkins, 2012). While elevated intraocular pressure (IOP) is a likely cause of optic nerve stress, many patients with apparently normal IOP develop glaucoma
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