Neurodegeneration in glaucoma: progression and calcium-dependent intracellular mechanisms

Abstract

Glaucoma is an age-related optic neuropathy involving sensitivity to ocular pressure. The disease is now seen increasingly as one of the central nervous system, as powerful new approaches highlight an increasing number of similarities with other age-related neurodegenerations such as Alzheimer's and Parkinson's. While the etiologies of these diseases are diverse, they involve many important common elements including compartmentalized programs of degeneration targeting axons, dendrites and finally cell bodies. Most age-related degenerations display early functional deficits that precede actual loss of neuronal substrate. These are linked to several specific neurochemical cascades that can be linked back to dysregulation of Ca(2+)-dependent processes. We are now in the midst of identifying similar cascades in glaucoma. Here we review recent evidence on the pathological progression of neurodegeneration in glaucoma and some of the Ca(2+)-dependent mechanisms that could underlie these changes. These mechanisms present clear implications for efforts to develop interventions targeting neuronal loss directly and make glaucoma an attractive model for both interrogating and informing other neurodegenerative diseases.

Figure 1. Degenerative Events Affecting the RGC Projection in Glaucoma

The RGC axon passes unmyelinated through a plexus of astrocytes in the nerve head that becomes neurochemically reactive in glaucoma. This is an established zone of vulnerability to IOP- and age-related stressors. All or nearly all RGCs project contralaterally to the superior colliculus, with small collaterals terminating in more anterior sites. These include the suprachiasmatic nucleus (SCN), lateral geniculate nucleus (LGN), and the pretectal nuclei: olivary pretectal (OPT), nucleus of optic tract (NOT), and posterior pretectal (PPT). A small fraction of RGCs also form ipsilateral projections. Early degenerative events in glaucoma include failure of anterograde transport and axonopathy, both of which progress from distal projection sites towards the optic nerve and retina. RGC axon terminals and their synapses eventually degrade. In the retina, degeneration includes loss of excitatory synapses and dendritic pruning.

Figure 2. Possible Ca²⁺-Dependent Mechanisms that Could Contribute to Glaucomatous Neurodegeneration

Multiple stressors relevant in glaucoma could disrupt homeostasis of RGC intracellular Ca²⁺. Two immediate consequences include oxidative stress and activation of calpains. Oxidative stress exacerbates Ca²⁺ dysregulation by reducing the capacity for mitochondria to buffer Ca²⁺, increasing release of Ca²⁺ from internal stores through interactions with the ryanodine (Ry) and inositol-triphosphate (IP3) receptors, and reducing clearance of intracellular Ca²⁺ by damaging membrane-bound maintenance proteins such as Ca²⁺ ATPase and the Na⁺/Ca²⁺ exchanger. Activated calpains increase the activity of cyclin-dependent kinase 5 (Cdk5), glycogen synthase kinase 2 (GSK3), and stress-activated protein kinases (SAPK) which phosphorylate cytoskeletal elements, slowing or stopping their axonal transport and promoting their aggregation. Calpains also directly degrade both cytoskeletal scaffolding and synapses. Cytoskeletal degradation and reduced mitochondrial function further compromise axonal transport and maintenance of dendrites, thus likely promoting synapse elimination. These degenerative components trigger the eventual apoptotic elimination of the cell body. Components in grey boxes represent likely targets not directly established for glaucoma.