Apoptotic retinal ganglion cell death in the DBA/2 mouse model of glaucoma

Reichstein, David; Ren, Lizhen; Filippopoulos, Theodoros; Mittag, Thomas W.; Danias, John

doi:10.1016/j.exer.2006.08.009

Cited by 75 publications

(68 citation statements)

References 30 publications

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“…This pattern is matched by pathologic process in the retina and optic nerve for both human glaucoma (33) and the DBA/2 mouse (8,14,24,25). The depletion of CTB transport from the retina to its primary projection site, the SC, follows a and aged (7-9 mo) rats is elevated acutely by 40% to 45% with microbead injection (circles) compared with saline solution in the opposite eye (diamonds).…”

Section: Discussionmentioning

confidence: 95%

“…1 C and D resemble sectorial vision loss in glaucoma, which extends to the RGC-rich central retina (23). Some degenerative markers in the aged DBA/2 optic nerve and retina also have this pattern (8,14,24,25). The area around the optic disk in the rodent contains the highest RGC density, like the human central retina (26).…”

Section: Resultsmentioning

confidence: 99%

“…Downstream apoptotic mechanisms contribute late in glaucoma (25,37,38), and axonal pathology precedes somatic degeneration (14-16, 24, 39, 40). Early distal transport deficits and axonal dystrophies are relevant in Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis (9)(10)(11).…”

Section: Discussionmentioning

confidence: 99%

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Distal axonopathy with structural persistence in glaucomatous neurodegeneration

Crish

Sappington

Inman

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

316

482

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An early hallmark of neuronal degeneration is distal transport loss and axon pathology. Glaucoma involves the degeneration of retinal ganglion cell (RGC) neurons and their axons in the optic nerve. Here we show that, like other neurodegenerations, distal axon injury appears early in mouse glaucoma. Where RGC axons terminate in the superior colliculus, reduction of active transport follows a retinotopic pattern resembling glaucomatous vision loss. Like glaucoma, susceptibility to transport deficits increases with age and is not necessarily associated with elevated ocular pressure. Transport deficits progress distal-to-proximal, appearing in the colliculus first followed by more proximal secondary targets and then the optic tract. Transport persists through the optic nerve head before finally failing in the retina. Although axon degeneration also progresses distal-to-proximal, myelinated RGC axons and their presynaptic terminals persist in the colliculus well after transport fails. Thus, distal transport loss is predegenerative and may represent a therapeutic target.axon transport | optic neuropathy | retinal ganglion cell | glaucoma | optic nerve

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Section: Discussionmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

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Distal axonopathy with structural persistence in glaucomatous neurodegeneration

Crish

Sappington

Inman

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

316

482

View full text Add to dashboard Cite

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“…Damage to the optic nerve due to elevated IOP and the loss of retinal ganglion cells (RGCs) are key sequelae of glaucoma, but amacrine cells (ACs), interneurons critical to retinal signaling, also appear to show significant injury (18)(19)(20)(21)(22). In mice, nearly all the RGC subtypes are homologously coupled via GJs (23), thereby providing the structural substrate for progressive, bystander-mediated cell death.…”

Section: Introductionmentioning

confidence: 99%

Targeting neuronal gap junctions in mouse retina offers neuroprotection in glaucoma

Akopian¹,

Kumar²,

Ramakrishnan³

et al. 2017

Journal of Clinical Investigation

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The progressive death of retinal ganglion cells and resulting visual deficits are hallmarks of glaucoma, but the underlying mechanisms remain unclear. In many neurodegenerative diseases, cell death induced by primary insult is followed by a wave of secondary loss. Gap junctions (GJs), intercellular channels composed of subunit connexins, can play a major role in secondary cell death by forming conduits through which toxic molecules from dying cells pass to and injure coupled neighbors. Here we have shown that pharmacological blockade of GJs or genetic ablation of connexin 36 (Cx36) subunits, which are highly expressed by retinal neurons, markedly reduced loss of neurons and optic nerve axons in a mouse model of glaucoma. Further, functional parameters that are negatively affected in glaucoma, including the electroretinogram, visual evoked potential, visual spatial acuity, and contrast sensitivity, were maintained at control levels when Cx36 was ablated. Neuronal GJs may thus represent potential therapeutic targets to prevent the progressive neurodegeneration and visual impairment associated with glaucoma.

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“…A number of studies demonstrated that ganglion cells are extremely vulnerable to exogenously applied NMDA, which inducesganglion cell degeneration.It has been also shown that NMDA receptor antagonists are neuroprotective in experimental glaucoma models [110][111][112][113][114][115][116][117]. NMDA receptors permit the influx of sodium ions (Na Although all NMDA receptors express the NR1 subunit [122,123,124], NR2 subunits are major determinants of the functional properties of NMDA receptor [125].…”

Section: A Nmda Receptorsmentioning

confidence: 99%