Glaucoma: Thinking in new ways—a rôle for autonomous axonal self-destruction and other compartmentalised processes?

doi:10.1016/j.preteyeres.2005.04.004

Progress in Retinal and Eye Research

Volume 24, Issue 6, November 2005, Pages 639-662

https://doi.org/10.1016/j.preteyeres.2005.04.004 Get rights and content

Abstract

Glaucoma is a common neurodegenerative disease that affects retinal ganglion cells (RGCs). Substantial effort is being expended to determine how RGCs die in glaucoma. As in other neurodegenerative diseases, the majority of effort focuses on characterising apoptotic self-destruct pathways. However, apoptosis is not the only self-destruct mechanism that may be activated in neurons. It is now known that neurons have distinct classes of self-destruct programme that are spatially compartmentalised. In addition to the well-described intracellular suicide machinery in the neuronal soma, responsible for apoptosis, there is another, molecularly distinct, self-destruct programme localised in the axon. Evidence also supports the existence of compartmentalised degeneration programmes in synapses and dendrites. RGCs are no exception to this. Recent data, from in vitro studies and from an inherited mouse model of glaucoma, suggest that molecularly distinct degenerative pathways underlie the destruction of RGC somata and RGC axons. In various neurodegenerative diseases, axons, dendrites and synapses often degenerate well before the cells die, and there is increasing evidence that this is important for the production of clinical symptoms and signs. We hypothesise that such compartmentalised and autonomous programmes are of critical importance in the pathophysiology of glaucoma, and we suggest that studies of these processes are essential for a complete understanding of this complex disease.

Section snippets

Glaucoma is a prevalent neurodegenerative disease

Glaucoma is a generic term for an aetiologically heterogeneous but clinically similar group of optic neuropathies causing progressive visual impairment that results from dysfunction and death of retinal ganglion cells (RGCs). It is the leading neurodegenerative cause of blindness, and the second leading cause of blindness worldwide (after cataract; Quigley, 1996, Quigley, 2002). Glaucoma affects all age groups but is more common in the elderly (Quigley and Vitale, 1997) and its prevalence is on

Compartmentalised self-destruction in neurons

To provide context when considering glaucoma susceptibility and RGC responses to glaucomatous stress, we suggest a new way of viewing RGC degeneration in glaucoma. In this view, the pathological response of an RGC is treated as a set of compartmentalised subcellular processes. These processes quite possibly have different triggers and take place in spatially distinct but connected parts of the neuron such as the synapse and axon. This view is gaining ground in other areas of neurodegeneration

Axonal self-destruction and glaucoma

Focal axonal injury is likely to be central to the development of glaucomatous RGC pathology. There is evidence (though no unequivocal demonstration as yet) that the site of initial injury of the RGC in glaucoma is the axon where it is vulnerable as it passes through the pores of the lamina cribrosa at the optic nerve head. For example, when IOP is experimentally raised there is reversible interruption of axonal transport at this location (Anderson and Hendrickson, 1974; Minckler et al., 1977,

Mechanisms of axonal self-destruction

Little is known of the molecular steps involved in axonal self-destruction and still less in the case of dendrites and synapses. For this reason, we are unable to discuss many specific examples directly pertaining to RGCs. Therefore, we bring together data from different neuronal cell types and models of degeneration and we extrapolate to RGCs where possible. The bias here in favour of axons reflects gaps in the available data rather than any reflection on our part of the perceived relative

Hypothetical models of compartmentalised degeneration in chronic and acute glaucoma

Can all of the preceding information help us towards a better understanding of what might be happening in glaucoma? We believe that it can. Although, with the current state of knowledge, it is necessary to be more speculative than we would prefer. Below, we detail two of a number of possible hypothetical models of compartmentalised degeneration in glaucoma. They underline a key rôle that RGC dysfunction due to compartmentalised degeneration might play in visual impairment. These ideas are

Future clinical issues

We have proposed that neuronal destruction in glaucoma is likely to be a modular process and that this provides a new framework in which glaucomatous optic neuropathy can be studied. While the above scenarios are hypothetical, they do at least take account of the modularity of the neuron and suggest that apoptosis need not necessarily be a critical component of early visual dysfunction in glaucoma. Can these concepts be incorporated into a rationale for neuroprotective strategies that will

Summary

In summary, we argue that it is time to divert significant effort in glaucoma research to a detailed study of compartmentalised RGC dysfunction. It is obviously not sufficient to think of a neuron as a single entity or of glaucoma as a single type of insult. Rather, it is necessary to consider the different structural and functional compartments of the neuron as well as the spatiotemporal nature and severity of the insult (so that the full range of possible lesions and their associated

Acknowledgements

We thank James Morgan, Martin Raff, Ian Murdoch, Phil Luthert and Adam Sillito for helpful comments on the manuscript and for advice. We also thank Felicia Farley for help in collating references. Graphics were drawn by Neil Randon.

The authors were supported by the following funding bodies: Medical Research Council UK; G84/5510 (AVW), National Eye Institute; F32-EY014515 (RTL), National Eye Institute; EY011721 (SWMJ). SWMJ is an Investigator of the Howard Hughes Medical Institute.

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Glaucoma: Thinking in new ways—a rôle for autonomous axonal self-destruction and other compartmentalised processes?

Abstract

Section snippets

Glaucoma is a prevalent neurodegenerative disease

Compartmentalised self-destruction in neurons

Axonal self-destruction and glaucoma

Mechanisms of axonal self-destruction

Hypothetical models of compartmentalised degeneration in chronic and acute glaucoma

Future clinical issues

Summary

Acknowledgements

Surv. Ophthalmol.

Am. J. Ophthalmol.

Ophthalmology

Exp. Neurol.

Methods Enzymol.

Brain Res.

Brain Res. Mol. Brain Res.

Trends Neurosci.

Dev. Biol.

Exp. Neurol.

Am. J. Ophthalmol.

Curr. Biol.

Brain Res. Brain Res. Rev.

Biochem. Biophys. Res. Commun.

Exp. Neurol.

Exp Eye Res.

J. Neurol. Sci.

Curr. Opin. Neurobiol.

Exp. Neurol.

Am. J. Pathol.

Prog. Retina Eye Res.

Ophthalm. Physiol. Opt.

Neuroscience

J. Neurol. Sci.

Neuron

Dev. Biol.

FEBS Lett.

The Advanced Glaucoma Intervention Study (AGIS): 7. The Relationship between control of intraocular pressure and visual field deterioration

Am. J. Ophthalmol.

Sensitivities of ocular tissues to acute pressure-induced ischemia

Arch. Ophthalmol.

Effect of intraocular pressure on rapid axoplasmic transport in monkey optic nerve

Invest. Ophthalmol.

Natural history of normal-tension glaucoma

Ophthalmology

Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration

Science

Selective innervation of retinorecipient brainstem nuclei by retinal ganglion cell axons regenerating through peripheral nerve grafts in adult rats

J. Neurosci.

Progressive motor neuron impairment in an animal model of familial amyotrophic lateral sclerosis

Muscle Nerve

Early striatal dendrite deficits followed by neuron loss with advanced age in the absence of anterograde cortical brain-derived neurotrophic factor

J. Neurosci.

The progressive nature of Wallerian degeneration in wild-type and slow Wallerian degeneration (WldS) nerves

BMC Neurosci.

Dendritic and synaptic alterations of hippocampal pyramidal neurones in scrapie-infected mice

Neuropathol. Appl. Neurobiol.

Physiological aspects of the circulation in the optic nerve

Missense mutation in the tubulin-specific chaperone E (Tbce) gene in the mouse mutant progressive motor neuronopathy, a model of human motoneuron disease

J. Cell Biol.

Organophosphorous neuropathy. I. A teased-fiber study of the spatio-temporal spread of axonal degeneraion

Am. J. Pathol.

Axonal L-type Ca2+ channels and anoxic injury in rat CNS white matter

J. Neurophysiol.

Early loss of dendritic spines in murine scrapie revealed by confocal analysis

Neuroreport

Charcot–Marie–Tooth disease neurofilament mutations disrupt neurofilament assembly and axonal transport

Hum. Mol. Genet.

Cytochrome c release and caspase activation in traumatic axonal injury

J. Neurosci.

Glial cells are increased proportionally in transgenic optic nerves with increased numbers of axons

J. Neurosci.

Local control of neurite development by nerve growth factor

Proc. Natl. Acad. Sci. USA

NGF and the local control of nerve terminal growth

J. Neurobiol.

Hyperthermia and hypoxia increase tolerance of retinal ganglion cells to anoxia and excitotoxicity

Invest. Ophthalmol. Vis. Sci.

Evidence of Wallerian degeneration in normal appearing white matter in the early stages of relapsing-remitting multiple sclerosis: a HMRS study