Critical pathogenic events underlying progression of neurodegeneration in glaucoma

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Abstract

Glaucoma is a common optic neuropathy with a complex etiology often linked to sensitivity to intraocular pressure. Though the precise mechanisms that mediate or transduce this sensitivity are not clear, the axon of the retinal ganglion cell appears to be vulnerable to disease-relevant stressors early in progression. One reason may be because the axon is generally thin for both its unmyelinated and myelinated segment and much longer than the thicker unmyelinated axons of other excitatory retinal neurons. This difference may predispose the axon to metabolic and oxidative injury, especially at distal sites where pre-synaptic terminals form connections in the brain. This idea is consistent with observations of early loss of anterograde transport at central targets and other signs of distal axonopathy that accompany physiological indicators of progression. Outright degeneration of the optic projection ensues after a critical period and, at least in animal models, is highly sensitive to cumulative exposure to elevated pressure in the eye. Stress emanating from the optic nerve head can induce not only distal axonopathy with aspects of dying back neuropathy, but also Wallerian degeneration of the optic nerve and tract and a proximal program involving synaptic and dendritic pruning in the retina. Balance between progressive and acute mechanisms likely varies with the level of stress placed on the unmyelinated axon as it traverses the nerve head, with more acute insult pushing the system toward quicker disassembly. A constellation of signaling factors likely contribute to the transduction of stress to the axon, so that degenerative events along the length of the optic projection progress in retinotopic fashion. This pattern leads to well-defined sectors of functional depletion, even at distal-most sites in the pathway. While ganglion cell somatic drop-out is later in progression, some evidence suggests that synaptic and dendritic pruning in the retina may be a more dynamic process. Structural persistence both in the retina and in central projection sites offers the possibility that intrinsic self-repair pathways counter pathogenic mechanisms to delay as long as possible outright loss of tissue.

Section snippets

Glaucoma and ocular pressure

Glaucoma is an etiologically complex collection of optic neuropathies. For the most prevalent primary forms, stressors related to age and intraocular pressure (IOP) lead to progressive degeneration of the retinal projection to the brain (Calkins and Horner, 2012; Nickells et al., 2012). This definition has evolved from many traditional viewpoints in two important ways. In terms of etiology, rather than linking exclusively to elevated IOP (ocular hypertension) for primary glaucoma, which remains

The RGC circuit

The human retina contains roughly 1.5 million RGCs distributed among several types defined by a unique combination of morphologically, neurochemical and physiological parameters (Hendry and Calkins, 1998). Specialized tuning of each RGC type emerges from the complex summation of signals derived from distinct presynaptic circuits. The canonical feed-forward circuit in the retina is comprised of three classes of excitatory, glutamatergic neurons: photoreceptors, bipolar cells, and of course RGCs.

Axonal transport deficits

Several intrinsic characteristics of the RGC axon likely render it susceptible to injury in glaucoma, independent of the many external factors in the axon's milieu that influence pathogenesis. Indeed, many of the earliest studies focused on the optic nerve head as a nexus of axon pathology, particularly in regard to depleted axoplasmic transport. These have been reviewed extensively before (Almasieh et al., 2012; Burgoyne, 2011; Knox et al., 2007; Whitmore et al., 2005). However, key issues are

Just passing through: the optic nerve head

A major goal has been to understand how factors extrinsic to the RGC axon as it passes through the nerve head contribute to a pathogenic environment and initiate and modulate progression (Hernandez, 2000; Moore and Goldberg, 2010; Osborne et al., 2001; Venkataraman et al., 2010; Vrabec and Levin, 2007). The extra-axonal milieu includes the vascular and glial architecture of the retina and optic nerve head, the scleral–laminar interface, and of course the lamina cribrosa or glial lamina as it is

Transduction of IOP stress

Our view of glaucoma has evolved considerably in recent years, from a disease involving mechanical injury due to elevated IOP to a disease involving a confluence of age- and IOP-related stressors acting upon a neural substrate. Glaucoma is largely axogenic, like other CNS diseases (Coleman, 2005; Whitmore et al., 2005), with axonal dysfunction in the optic projecting occurring prior to outright degeneration and loss of tissue (Fig. 8). This progression could explain why, in non-human primates,

Acknowledgments

The author wishes to dedicate this article to Thomas Brunner, for his unwavering and innovative support of biomedical research through the Glaucoma Research Foundation and its Catalyst for a Cure program. The author also expresses his sincerest gratitude to many gifted and dedicated collaborators over the years, in particular Catalyst for a Cure members Rebecca Sappington, Philip Horner, Samuel Crish, Denise Inman, Monica Vetter, Alejandra Bosco, Martin Wax, and Nicholas Marsh-Armstrong.

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    Percentage contribution of each author: David J. Calkins: 100%.

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