Critical pathogenic events underlying progression of neurodegeneration in glaucoma
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%.