Susceptibility to Neurodegeneration in a Glaucoma Is Modified by Bax Gene Dosage

Libby, Richard T.; Li, Yan; Savinova, Olga V.; Barter, Joseph W.; Smith, Richard; Nickells, Robert W.; John, Simon W. M.

doi:10.1371/journal.pgen.0010004

Cited by 344 publications

(441 citation statements)

References 69 publications

Supporting

Mentioning

419

Contrasting

Order By: Relevance

“…Severely (SEV) affected nerves have extensive axon damage throughout the nerve and obvious axon loss. Axon numbers are significantly different between optic nerves of each damage level (39).…”

Section: Methodsmentioning

confidence: 90%

“…The method of preparing, staining, and analyzing optic nerves for damage has been previously described and validated (5,8,20,27,34,39). In brief, cross-sections of optic nerve are stained with paraphenylenediamine (PPD), which stains all myelin sheaths but darkly stains the axoplasm of injured or dying axons.…”

Section: Methodsmentioning

confidence: 99%

“…Collectively, the 10.5-and 12-mo data suggest that longer-term IOP elevation and its associated stresses induce damaging processes that overcome the early protective effects of C3. In D2 glaucoma, apoptosis of RGC somas can be uncoupled from axon degeneration, with specific molecules having differential effects on axons and somas (39). There is no evidence that C3 deficiency differentially affects RGC axons and somas; for example, C3-deficient eyes with severe axon loss also have severe soma loss (Fig.…”

Section: Up-regulation Of Complement Component C3 Is An Early Immunementioning

confidence: 99%

See 2 more Smart Citations

Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective

Harder

Braine

Williams

et al. 2017

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

103

View full text Add to dashboard Cite

Various immune response pathways are altered during early, predegenerative stages of glaucoma; however, whether the early immune responses occur secondarily to or independently of neuronal dysfunction is unclear. To investigate this relationship, we used the Wld s allele, which protects from axon dysfunction. We demonstrate that DBA/2J.Wld s mice develop high intraocular pressure (IOP) but are protected from retinal ganglion cell (RGC) dysfunction and neuroglial changes that otherwise occur early in DBA/2J glaucoma. Despite this, immune pathways are still altered in DBA/2J.Wld s mice. This suggests that immune changes are not secondary to RGC dysfunction or altered neuroglial interactions, but may be directly induced by the increased strain imposed by high IOP. One early immune response following IOP elevation is up-regulation of complement C3 in astrocytes of DBA/2J and DBA/ 2J.Wld s mice. Unexpectedly, because the disruption of other complement components, such as C1Q, is protective in glaucoma, C3 deficiency significantly increased the number of DBA/2J eyes with nerve damage and RGC loss at an early time point after IOP elevation. Transcriptional profiling of C3-deficient cultured astrocytes implicated EGFR signaling as a hub in C3-dependent responses. Treatment with AG1478, an EGFR inhibitor, also significantly increased the number of DBA/2J eyes with glaucoma at the same early time point. These findings suggest that C3 protects from early glaucomatous damage, a process that may involve EGFR signaling and other immune responses in the optic nerve head. Therefore, therapies that target specific components of the complement cascade, rather than global inhibition, may be more applicable for treating human glaucoma.G laucoma is a common disorder characterized by the loss of retinal ganglion cells (RGCs) and degeneration of the optic nerve (1-3). Intraocular pressure (IOP) elevation is a major risk factor for developing glaucoma (4). Harmful IOP leads to changes in immune response pathways in nonneuronal cells, such as astrocytes and microglia/monocytes (5-9). Similar changes occur in many neurodegenerative diseases, including Parkinson's disease (10), Alzheimer's disease (11), and Huntington's disease (12). In glaucoma, immune responses are known to occur at predegenerative stages (5, 8), but key questions remain unanswered (2, 13-15). It is not known whether the earliest immune responses are protective or damaging, or which events irreversibly damage the optic nerve. Moreover, it is not known whether the immune responses are secondary to RGC dysfunction or occur independently, possibly as a more direct result of IOP elevation.In glaucoma, an early insult to RGC axons occurs where they exit the eye in the optic nerve head (ONH) (16)(17)(18)(19)(20). Modeling shows that an increase in IOP inside the eye leads to increased strain in this critical region (21,22). To understand the molecular responses occurring during glaucoma, gene expression profiles of human lamina astrocytes and ONH tissue from animal models hav...

show abstract

Section: Methodsmentioning

confidence: 90%

Section: Methodsmentioning

confidence: 99%

Section: Up-regulation Of Complement Component C3 Is An Early Immunementioning

confidence: 99%

See 1 more Smart Citation

Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective

Harder

Braine

Williams

et al. 2017

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

103

View full text Add to dashboard Cite

show abstract

“…Studies have also indicated axonopathy as an early feature in neurodegenerative diseases associated with excitotoxicity [13-16]. It is unclear whether the nerve degeneration associated with excitotoxicity is due to primary insult at the perikaryal level in the grey matter or a primary excitotoxic injury in the white matter.…”

Section: Introductionmentioning

confidence: 99%

Wallerian-like axonal degeneration in the optic nerve after excitotoxic retinal insult: an ultrastructural study

et al. 2010

View full text Add to dashboard Cite

BackgroundExcitotoxicity is involved in the pathogenesis of a number neurodegenerative diseases, and axonopathy is an early feature in several of these disorders. In models of excitotoxicity-associated neurological disease, an excitotoxin delivered to the central nervous system (CNS), could trigger neuronal death not only in the somatodendritic region, but also in the axonal region, via oligodendrocyte N-methyl-D-aspartate (NMDA) receptors. The retina and optic nerve, as approachable regions of the brain, provide a unique anatomical substrate to investigate the "downstream" effect of isolated excitotoxic perikaryal injury on central nervous system (CNS) axons, potentially providing information about the pathogenesis of the axonopathy in clinical neurological disorders.Herein, we provide ultrastructural information about the retinal ganglion cell (RGC) somata and their axons, both unmyelinated and myelinated, after NMDA-induced retinal injury. Male Sprague-Dawley rats were killed at 0 h, 24 h, 72 h and 7 days after injecting 20 nM NMDA into the vitreous chamber of the left eye (n = 8 in each group). Saline-injected right eyes served as controls. After perfusion fixation, dissection, resin-embedding and staining, ultrathin sections of eyes and proximal (intraorbital) and distal (intracranial) optic nerve segments were evaluated by transmission electron tomography (TEM).ResultsTEM demonstrated features of necrosis in RGCs: mitochondrial and endoplasmic reticulum swelling, disintegration of polyribosomes, rupture of membranous organelle and formation of myelin bodies. Ultrastructural damage in the optic nerve mimicked the changes of Wallerian degeneration; early nodal/paranodal disturbances were followed by the appearance of three major morphological variants: dark degeneration, watery degeneration and demyelination.ConclusionNMDA-induced excitotoxic retinal injury causes mainly necrotic RGC somal death with Wallerian-like degeneration of the optic nerve. Since axonal degeneration associated with perikaryal excitotoxic injury is an active, regulated process, it may be amenable to therapeutic intervention.

show abstract

“…1 In fact BAX activation appears to require at least one of these pro-apoptotic chaperones during development and after many apoptotic insults. 2 Retinal ganglion cells (RGCs) die by a BAX-dependent mechanism in development and after axonal injury, 3 a key insult in many neurodegenerations. During development BAX-dependent death of RGCs requires BBC3 (Harder and Libby 4 and Supplementary Figure 1A); however, the molecules controlling BAX activation after axonal injury are unknown.…”

mentioning

confidence: 99%

Deficiency in Bim, Bid and Bbc3 (Puma) do not prevent axonal injury induced death

Harder

Libby

2012

Cell Death Differ

View full text Add to dashboard Cite

Susceptibility to Neurodegeneration in a Glaucoma Is Modified by Bax Gene Dosage

Cited by 344 publications

References 69 publications

Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective

Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective

Wallerian-like axonal degeneration in the optic nerve after excitotoxic retinal insult: an ultrastructural study

Deficiency in Bim, Bid and Bbc3 (Puma) do not prevent axonal injury induced death

Contact Info

Product

Resources

About