[HTML][HTML] The cell and molecular biology of glaucoma: mechanisms of retinal ganglion cell death

RW Nickells - Investigative ophthalmology & visual science, 2012 - iovs.arvojournals.org
Investigative ophthalmology & visual science, 2012iovs.arvojournals.org
Glaucomatous optic neuropathies are characterized by the progressive degeneration of the
optic nerve and retinal ganglion cells. Conceptually, the process of ganglion cell loss can be
considered a series of autonomous, self-destructing pathways. 1 Retinal ganglion cells, for
example, can be divided into basic regions, including the axon and synapse, the dendritic
arbor, and the cell body. Each of these compartments, although contiguous with one
another, can independently degenerate. A current model of glaucomatous pathogenesis …
Glaucomatous optic neuropathies are characterized by the progressive degeneration of the optic nerve and retinal ganglion cells. Conceptually, the process of ganglion cell loss can be considered a series of autonomous, self-destructing pathways. 1 Retinal ganglion cells, for example, can be divided into basic regions, including the axon and synapse, the dendritic arbor, and the cell body. Each of these compartments, although contiguous with one another, can independently degenerate. A current model of glaucomatous pathogenesis suggests that the first compartment that is affected by intraocular pressure (IOP)–induced damage is the axon. The site of this damage is the laminar region of the eye, where the axons of the retinal ganglion cells exit the globe as they enter the optic nerve.
The process of the damage to the axons is a matter of great speculation and ongoing research efforts and is not the principal subject of this essay. Basically, however, the strain placed on this region by elevated IOP causes molecular and functional changes to the resident cell population of the tissue. The principal cell population is made up of astrocytes, but lamina cribrosacytes, which have molecular profiles that are distinct from those of astrocytes, are also thought to reside there. One mechanism of axonal damage may be loss of support functions from the resident glial cells. Loss of energy support, for example, may lead to axons becoming unable to sustain energydependent processes such as axonal transport. Whatever the mechanism, rodent models of chronic glaucoma suggest that axon dysfunction and subsequent degeneration, are early events in the pathology of retinal ganglion cells. 2, 3 The level of damage to most axons is probably subacute, meaning that they are likely to retain connection and some level of communication with the ganglion cell soma. The evidence for subacute damage is that axons in glaucomatous mice degenerate by the dieback phenomenon at least in one model of glaucoma, 2 although several studies have suggested that a proportion of axons also exhibit more severe Wallerian degeneration. 3, 4 Dieback is the process of degeneration that begins at the distal most point of the axon (the synapse) and progresses toward the cell body. This process could occur even if the initial site of damage is proximal to the cell body. A more acute injury, such as axotomy, would result in simultaneous degeneration of the axon throughout its length by Wallerian degeneration.
ARVO Journals