Progressive Ganglion Cell Degeneration Precedes Neuronal Loss in a Mouse Model of Glaucoma

Buckingham, Brian P.; Inman, Denise M.; Lambert, Wendi S.; Oglesby, Ericka; Calkins, David J.; Steele, Matt; Vetter, Monica L.; Marsh-Armstrong, Nicholas; Horner, Philip J.

doi:10.1523/jneurosci.4443-07.2008

Cited by 372 publications

(382 citation statements)

References 53 publications

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“…2), so additional pathogenic mechanisms must be at work early (30,36). Retrograde transport from the SC to the retina in the DBA/2 is maintained at 20% to 30% capacity up to 18 mo of age (16,17). Anterograde transport is challenged considerably earlier, with complete failure to the SC at 11 to 12 mo and to all RGC targets in the brain after 12 mo (Figs.…”

Section: Discussionmentioning

confidence: 99%

“…To visualize RGC axons in layer III of the SC and determine SC volume, we used the myelin marker Black Gold II (Histochem) (31) in serial 50-μm SC sections. For quantifying axons in the optic nerve, segments near the eye (proximal) and optic chiasm (distal) were quantified as described (16,30). For scoring RGCs containing CTB, retinas were sampled in confocal micrographs using a grid with 318 × 318-μm fields every 636 μm.…”

Section: Methodsmentioning

confidence: 99%

“…DBA/2 mice present agedependent elevations in IOP as a result of pigmentary dispersion in the anterior eye that are linked to RGC degeneration (14,15). Retrograde transport from the SC persists as late as 18 months of age in the DBA/2 mouse (16,17). Here we examine anterograde transport from the retina to the superior colliculus (SC), the primary projection site for RGCs in the rodent brain (18,19).…”

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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.

312

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: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

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.

312

482

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“…As Brn3 is rapidly down-regulated upon injury, we evaluated γ-synuclein as a marker based on the specific RGC expression observed by in situ hybridization (19,20). An antibody against γ-synuclein displayed strong nuclear staining that colabeled, but was not limited to, all Brn3-positive nuclei (Fig.…”

Section: G K O and R)mentioning

confidence: 99%

DLK initiates a transcriptional program that couples apoptotic and regenerative responses to axonal injury

Watkins¹,

Wang²,

Huntwork‐Rodriguez³

et al. 2013

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

277

427

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The cell intrinsic factors that determine whether a neuron regenerates or undergoes apoptosis in response to axonal injury are not well defined. Here we show that the mixed-lineage dual leucine zipper kinase (DLK) is an essential upstream mediator of both of these divergent outcomes in the same cell type. Optic nerve crush injury leads to rapid elevation of DLK protein, first in the axons of retinal ganglion cells (RGCs) and then in their cell bodies. DLK is required for the majority of gene expression changes in RGCs initiated by injury, including induction of both proapoptotic and regeneration-associated genes. Deletion of DLK in retina results in robust and sustained protection of RGCs from degeneration after optic nerve injury. Despite this improved survival, the number of axons that regrow beyond the injury site is substantially reduced, even when the tumor suppressor phosphatase and tensin homolog (PTEN) is deleted to enhance intrinsic growth potential. These findings demonstrate that these seemingly contradictory responses to injury are mechanistically coupled through a DLK-based damage detection mechanism.A xonal damage results in significant neuronal cell death and axon degeneration, often leading to permanent functional deficits. For example, optic nerve crush rapidly induces a stress response in retinal ganglion cells (RGCs) that includes profound alterations in gene expression patterns (1) and ultimately leads to apoptosis of these neurons (2). As axon injury may occur a significant distance from the cell body, it has been proposed that retrograde molecular motors play a critical role in conveying damage signals to the nucleus, allowing the cell to respond to damage (3). Attenuation of this transport mechanism has been shown to reduce degeneration, suggesting that the ability of the nucleus to detect an insult is an essential component of the injury response (4).Recent data suggest that dual leucine zipper kinase (DLK) is an essential component of the neuronal response to axon damage. DLK protein is present in axons, and protein levels are increased in response to axonal injury (5). Loss of DLK has been shown to protect distal axons from Wallerian degeneration (6) and to abrogate stress-induced retrograde c-Jun N-terminal kinase (JNK) signaling through interaction with the scaffolding protein JNK-interacting protein 3 (JIP3) (7-9). In many instances, injury-induced JNK activation in neurons results in apoptosis through phosphorylation of activator protein 1 (AP-1) transcription factors such as c-Jun, which initiates a proapoptotic gene expression program (10, 11). Consistent with this, genetic deletion of JNK2 and/or JNK3 is sufficient to protect neurons from degeneration in a range of CNS injury models, including axotomy (12-14), although the role of DLK in these contexts is not known.In contrast, DLK has been shown to regulate axon regeneration after axonal injury in adult peripheral nerves (9) and invertebrate systems (5, 15). The mechanism underlying the divergence between these apoptotic and reg...

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“…Thus, DBA/2J mouse represents a good model to investigate mechanisms involved in progressive retinal neurodegeneration from a phase characterized by ocular hypertension to glaucoma. We investigated DBA/2J mice at an early stage of degeneration characterized by ocular hypertension with impairment of retinal responses to visual stimuli (7 months of age) without RGC death, at an intermediate stage characterized by ON atrophy and RGC degeneration (10-12 months of age) and at a later stage with massive RGC death and soma loss [6].…”

Section: Introductionmentioning

confidence: 99%

Changes in BDNF and MAPK Signaling Pathways in Experimental Glaucoma

Fabiani¹,

Cerri²

2016

J Clin Exp Ophthalmol

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Glaucoma is currently recognized to be a multifactorial, progressive, neurodegenerative disorder. It is characterized by the retinal ganglion cells (RGCs) loss of axons as well as optic nerve atrophy, progressive degeneration of RGCs till cell death. In this work, we used DBA/2J mice as a model of spontaneous glaucoma and we investigated the involvement of BDNF and Mitogen-Activated Protein Kinases (MAPK) pathways in correlation with IOP elevation and progression of neurodegenerative processes in the retina of DBA/2J mice. In particular, we performed western blot analysis to study retinal levels of the BDNF and its receptor, TrkB, and to better understand possible modulation of p38 MAPK and ERK1/2 activation at different stages of retinal degeneration in DBA/2J mice. We showed that BDNF starts to decrease already at an early stage in correspondence to IOP elevation (7 months of age). MAPKs, in particular p38 MAPK and ERK1/2, appeared maximally affected at more advanced stages of neurodegeneration (10-12 and 18 months of age) characterized by RGC degeneration and death, optic nerve atrophy. Thus, BDNF signaling and MAPKs are differentially activated at different stages of retinal degeneration in DBA/2J mice, a murine model of glaucoma.

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Progressive Ganglion Cell Degeneration Precedes Neuronal Loss in a Mouse Model of Glaucoma

Cited by 372 publications

References 53 publications

Distal axonopathy with structural persistence in glaucomatous neurodegeneration

Distal axonopathy with structural persistence in glaucomatous neurodegeneration

DLK initiates a transcriptional program that couples apoptotic and regenerative responses to axonal injury

Changes in BDNF and MAPK Signaling Pathways in Experimental Glaucoma

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