The molecular basis of retinal ganglion cell death in glaucoma (original) (raw)
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Progressive Ganglion Cell Degeneration Precedes Neuronal Loss in a Mouse Model of Glaucoma
The Journal of Neuroscience, 2008
Glaucoma is characterized by retinal ganglion cell (RGC) pathology and a progressive loss of vision. Previous studies suggest RGC death is responsible for vision loss in glaucoma, yet evidence from other neurodegenerative diseases suggests axonal degeneration, in the absence of neuronal loss, can significantly affect neuronal function. To characterize RGC degeneration in the DBA/2 mouse model of glaucoma, we quantified RGCs in mice of various ages using neuronal-specific nuclear protein (NeuN) immunolabeling, retrograde labeling, and optic nerve axon counts. Surprisingly, the number of NeuN-labeled RGCs did not decline significantly until 18 months of age, at which time a significant decrease in RGC somal size was also observed. Axon dysfunction and degeneration occurred before loss of NeuN-positive RGCs, because significant declines in RGC number assayed by retrograde tracers and axon counts were observed at 13 months. To examine whether axonal dysfunction/degeneration affected gen...
International Journal of Molecular Sciences
Retinal ganglion cells (RGCs) are a population of neurons of the central nervous system (CNS) extending with their soma to the inner retina and with their axons to the optic nerve. Glaucoma represents a group of neurodegenerative diseases where the slow progressive death of RGCs results in a permanent loss of vision. To date, although Intra Ocular Pressure (IOP) is considered the main therapeutic target, the precise mechanisms by which RGCs die in glaucoma have not yet been clarified. In fact, Primary Open Angle Glaucoma (POAG), which is the most common glaucoma form, also occurs without elevated IOP. This present review provides a summary of some pathological conditions, i.e., axonal transport blockade, glutamate excitotoxicity and changes in pro-inflammatory cytokines along the RGC projection, all involved in the glaucoma cascade. Moreover, neuro-protective therapeutic approaches, which aim to improve RGC degeneration, have also been taken into consideration.
The Journal of Neuroscience, 2008
Little is known about molecular changes occurring within retinal ganglion cells (RGCs) before their death in glaucoma. Taking advantage of the fact that γ-synuclein (Sncg) mRNA is expressed specifically and highly in adult mouse RGCs, we show in the DBA/2J mouse model of glaucoma that there is not only a loss of cells expressing this gene, but also a downregulation of gene expression of Sncg and many other genes within large numbers of RGCs. This downregulation of gene expression within RGCs occurs together with reductions in FluoroGold (FG) retrograde transport. Surprisingly, there are also large numbers of Sncg-expressing cells without any FG labeling, and among these many that have a marker previously associated with disconnected RGCs, accumulation of phosphorylated neurofilaments in their somas. These same diseased retinas also have large numbers of RGCs that maintain the intraocular portion while losing the optic nerve portion of their axons, and these disconnected axons termin...
Neurotrophin roles in retinal ganglion cell survival: Lessons from rat glaucoma models
Experimental Eye Research, 2009
The neurotrophin (NT) hypothesis proposes that the obstruction of retrograde transport at the optic nerve head results in the deprivation of neurotrophic support to retinal ganglion cells (RGC) leading to apoptotic cell death in glaucoma. An important corollary to this concept is the implication that appropriate enhancement of neurotrophic support will prolong the survival of injured RGC indefinitely. This hypothesis is, perhaps, the most widely recognized theory to explain RGC loss resulting from exposure of the eye to elevated intraocular pressure (IOP). Recent studies of NT signaling using rat glaucoma models, have examined the endogenous responses of the retina to pressure exposure as well as studies designed to augment NT signaling in order to rescue RGC from apoptosis following pressure-induced injury. The examination of these studies in this review reveals a number of consistent observations and provides direction for further investigations of this hypothesis.
SUMMARYRetinal ganglion cell (RGC) death is the hallmark of glaucoma. Axonal injury is thought to precede RGC loss in glaucoma, and thus studies using an optic nerve (ON) crush model have been widely used to investigate mechanisms of cell death that are common to both conditions. Prior work has focused on the involvement of caspases in RGC death, but little is known about the contribution of other forms of cell death such as necrosis. In this study we show that receptor interacting protein (RIP) kinase-mediated necrosis normally plays a role in RGC death and acts in concert with caspase-dependent apoptosis. The expression of RIP3, a key activator of RIP1 kinase, as well as caspase activity, increased following ON injury. Caspase inhibition alone failed to provide substantial protection to injured RGCs and unexpectedly exacerbated necrosis. In contrast, pharmacologic or genetic inhibition of RIP kinases in combination with caspase blockade delayed both apoptotic and necrotic RGC deat...
Retinal ganglion cells: dying to survive.
ABSTRACT This review examines the maturation of the retinal ganglion cell (RGC) population within the nascent retina. Apoptosis, a form of programmed cell death prevalent throughout the developing central nervous system (CNS), is evident in the growth of RGCs within the ganglion cell layer. These cells provide an accessible and illuminating platform to elucidate the apoptotic pathways present in the developing CNS and the role this form of cell death plays in RGC growth. This article focuses on the seminal stages of RGC development and the role played by neurotrophic factors and apoptosis in this process.
Programmed cell death of retinal ganglion cells during experimental glaucoma
Experimental Eye Research, 1995
The death of retinal ganglion cells during glaucoma is thought to result from damage to their axons as they exit the eye through the lamina cribrosa. In this study, intraocular pressure in the rat was increased to twice the normal averge by cauterizing two limbal-derived veins. To investigate whether retinal ganglion cells in the glaucomatous eye follow an apoptotic type of death, DNA breaks in nuclei were labeled in situ, using a method that specifically incorporates biotinylated deoxynucleotides by exogenous terminal deoxynucleotidyl transferase to the 3′-OH ends of DNA. The active nature of the death mechanism was demonstrated by the reduction in numbers of biotin-labeled nuclei after administration of the protein synthesis inhibitor, cycloheximide. Our results suggest that retinal ganglion cells of the adult rat die through apoptosis when the intraocular pressure is markedly increased. This raises new possibilities in the treatment of glaucomatous damage to the retina, by the potential interruptibility of a program for neuronal death.
Current Trends in Glaucoma: What about Neuroprotection?
Glaucoma is an optic neuropathy, considered as the second leading cause of blindness worldwide. Glaucoma is characterized by selective death of retinal ganglion cells (RGC) and a progressive loss of vision. Elevated intraocular pressure (IOP) is one of the most important risk factors for developing glaucoma, so we mainly focus on lowering IOP to arrest the progression of glaucoma. However, many patients continue to demonstrate a clinically downhill course despite the control of initially raised IOP. In fact, some patients develop what is called Normal Tension Glaucoma, not associated to an increased IOP. This emphasizes that several pressure-independent mechanisms are responsible for the development and progression of glaucomatous neuropathy and that high intraocular pressure (IOP) and vascular insufficiency in the optic nerve head are only risk factors for the development of glaucoma, and are not the only target for the treatment of glaucoma. The reason is that the process of RGC death is thought to be biphasic, and the primary injury is followed by a slower secondary degeneration related to a noxious environment surrounding the apoptotic cells. This environment is characterized by changes in the extra-cellular ionic concentrations, increased amounts of free radicals, neurotrophins depletion and increased glutamate induced excitotoxicity due to high extra-cellular glutamate levels, which binds