Excitotoxic Death of Retinal Neurons<i>In Vivo</i>Occurs via a Non-Cell-Autonomous Mechanism

Lebrun-Julien, Frédéric; Duplan, Laure; Pernet, Vincent; Osswald, Ingrid K.; Sapieha, Przemyslaw; Bourgeois, Philippe; Dickson, Kathleen M.; Bowie, Derek; Barker, Philip A.; Polo, Adriana Di

doi:10.1523/jneurosci.0831-09.2009

Cited by 165 publications

(185 citation statements)

References 98 publications

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“…Therefore, it is possible that proNGF induces cell death in the adult retina by directly binding to a p75 NTR -sortilin complex on adult RGCs. This is very unlikely, however, because examination of p75 NTR expression in the adult rodent retina using light and electron microscopy has established that retinal p75 NTR expression is confined to Müller glial cells (9,(12)(13)(14)(15). A recent study reported that sortilin is expressed by Müller glia in the adult retina (16), and the data shown here indicate that NRAGE is also expressed in these glial cells.…”

Section: Resultsmentioning

confidence: 72%

“…A simple model to explain these results would have proNGF binding to the p75 NTR -sortilin complex on the surface of RGCs that in turn activates a cell-autonomous, NRAGEdependent proapoptotic pathway. However, it has been reported that Müller glia are the only cells that express p75 NTR in the adult retina (9,(12)(13)(14)(15), implying that proNGF killing of RGCs may involve a more complex mechanism. To confirm the p75 NTR expression pattern in the adult mouse retina, RGCs were retrogradely labeled with fluorogold and then stained with antibodies specific for p75 NTR .…”

Section: Resultsmentioning

confidence: 99%

“…Importantly, this mechanism of cell death may play a role in RGC loss after injury. For example, RGCs lacking TNFR1 are protected following optic nerve crush (39), and we recently showed that TNFα-mediated increase in cell surface Ca 2+ -permeable AMPARs leads to RGC loss in vivo (15).…”

Section: Resultsmentioning

confidence: 99%

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ProNGF induces TNFα-dependent death of retinal ganglion cells through a p75 ^NTR non-cell-autonomous signaling pathway

Lebrun-Julien

Bertrand

Backer

et al. 2010

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

110

100

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Neurotrophin binding to the p75 neurotrophin receptor (p75 NTR ) activates neuronal apoptosis following adult central nervous system injury, but the underlying cellular mechanisms remain poorly defined. In this study, we show that the proform of nerve growth factor (proNGF) induces death of retinal ganglion cells in adult rodents via a p75 NTR -dependent signaling mechanism. Expression of p75 NTR in the adult retina is confined to Müller glial cells; therefore we tested the hypothesis that proNGF activates a non-cellautonomous signaling pathway to induce retinal ganglion cell (RGC) death. Consistent with this, we show that proNGF induced robust expression of tumor necrosis factor alpha (TNFα) in Müller cells and that genetic or biochemical ablation of TNFα blocked proNGF-induced death of retinal neurons. Mice rendered null for p75 NTR , its coreceptor sortilin, or the adaptor protein NRAGE were defective in proNGF-induced glial TNFα production and did not undergo proNGF-induced retinal ganglion cell death. We conclude that proNGF activates a non-cell-autonomous signaling pathway that causes TNFα-dependent death of retinal neurons in vivo.T he four mammalian neurotrophins comprise a family of related secreted factors that are required for differentiation, survival, development, and death of specific populations of neurons and nonneuronal cells. Neurotrophins are produced as proforms of ∼240 amino acids that are cleaved by furins and proconvertases to yield products of ∼120 amino acids. Recent studies have indicated that nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) can be secreted as proforms in the central nervous system (CNS) (1-3) and demonstrated that proneurotrophins can function as potent apoptosis-inducing ligands both in vitro and in vivo (4). However, the precise mechanisms by which proneurotrophins lead to neuronal death are poorly defined.The biological effects of neurotrophins are mediated by binding to TrkA, TrkB, and TrkC receptor tyrosine kinases and to the p75 neurotrophin receptor (p75 NTR ). Trk receptors respond preferentially to mature neurotrophins whereas proneurotrophins exert their apoptotic effect via a receptor complex that contains p75 NTR and sortilin (5). The precise signaling cascades evoked by occupancy of the p75 NTR -sortilin complex remain to be elucidated, but several lines of evidence indicate that NRIF and NRAGE adaptor proteins play key roles in death signaling cascades evoked by p75 NTR (6, 7).Previous studies have shown that neurotrophins induce cell death via p75 NTR during early retinal development (8). p75 NTR has also been implicated in light-induced photoreceptor death in adult rodents in vivo (9) and a proNGF-p75 NTR link has been proposed to facilitate apoptosis in a retinal cell line (10). Here, we investigate the role of proNGF in the adult retina and demonstrate that proNGF promotes death of retinal ganglion cells (RGCs) in vivo. Importantly, proNGF-induced RGC loss is indirect and requires the p75 NTRdependent production of tumor necrosis...

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Section: Resultsmentioning

confidence: 72%

Section: Resultsmentioning

confidence: 99%

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ProNGF induces TNFα-dependent death of retinal ganglion cells through a p75 ^NTR non-cell-autonomous signaling pathway

Lebrun-Julien

Bertrand

Backer

et al. 2010

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

110

100

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“…However, in NMDAdamaged retinas, we did not find decreases in IL1β, IL6 or TNFα in response to Dex, even though the microglial reactivity was suppressed. In the rodent retina, Müller glia are known to produce pro-inflammatory cytokines in response to NMDA treatment, and elevated production of TNFα can render neurons more susceptible to excitotoxic damage (Lebrun-Julien et al, 2009). The mechanisms by which Dex suppresses the reactivity of microglia in NMDAdamaged retinas remain uncertain, but are likely to be secondary to signaling in Müller glia given that GCR was not detected in microglia.…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid receptors in the retina, Müller glia and the formation of Müller glia-derived progenitors

2014

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Identification of the signaling pathways that influence the reprogramming of Müller glia into neurogenic retinal progenitors is key to harnessing the potential of these cells to regenerate the retina. Glucocorticoid receptor (GCR) signaling is commonly associated with anti-inflammatory responses and GCR agonists are widely used to treat inflammatory diseases of the eye, even though the cellular targets and mechanisms of action in the retina are not well understood. We find that signaling through GCR has a significant impact upon the ability of Müller glia to become proliferating Müller glia-derived progenitor cells (MGPCs). The primary amino acid sequence and pattern of GCR expression in the retina is highly conserved across vertebrate species, including chickens, mice, guinea pigs, dogs and humans. In all of these species we find GCR expressed by the Müller glia. In the chick retina, we find that GCR is expressed by progenitors in the circumferential marginal zone (CMZ) and is upregulated by Müller glia in acutely damaged retinas. Activation of GCR signaling inhibits the formation of MGPCs and antagonizes FGF2/MAPK signaling in the Müller glia. By contrast, we find that inhibition of GCR signaling stimulates the formation of proliferating MGPCs in damaged retinas, and enhances the neuronal differentiation while diminishing glial differentiation. Given the conserved expression pattern of GCR in different vertebrate retinas, we propose that the functions and mechanisms of GCR signaling are highly conserved and are mediated through the Müller glia. We conclude that GCR signaling directly inhibits the formation of MGPCs, at least in part, by interfering with FGF2/MAPK signaling.

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“…For example, a recent study demonstrated that Müller cells are extremely sensitive to an acute excitotoxic insult and respond by upregulating TNF-a, which then mediates RGC loss. 103 In the case of chronic, neurodegenerative diseases where an excitotoxic component is thought to be involved, such as in glaucoma, blockade of glutamate receptors may not ameliorate disease progression unless other damaging molecules (for example, glia-derived TNF-a) are also inhibited. The molecular pathways involved in RGC excitotoxicity have been targeted using drugs and pharmacological agents, but, so far, gene therapy has not been explored.…”

Section: Inhibition Of Apoptotic Pathways and Manipulation Of Mitochomentioning

confidence: 99%

Gene therapy for retinal ganglion cell neuroprotection in glaucoma

Wilson

Polo

2011

Gene Ther

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Glaucoma is the leading cause of irreversible blindness worldwide. The primary cause of glaucoma is not known, but several risk factors have been identified, including elevated intraocular pressure and age. Loss of vision in glaucoma is caused by the death of retinal ganglion cells (RGCs), the neurons that convey visual information from the retina to the brain. Therapeutic strategies aimed at delaying or halting RGC loss, known as neuroprotection, would be valuable to save vision in glaucoma. In this review, we discuss the significant progress that has been made in the use of gene therapy to understand mechanisms underlying RGC degeneration and to promote the survival of these neurons in experimental models of optic nerve injury. Gene Therapy (2012) 19, 127-136; doi:10.1038/gt.2011; published online 6 October 2011Keywords: retinal ganglion cell; neuroprotection; glaucoma NEUROPROTECTION IN GLAUCOMA: RATIONALE AND CURRENT LIMITATIONS Adult-onset glaucoma is an optic neuropathy that affects more than 50 million people around the world, with 47 million having bilateral (both eyes) blindness due to this disease. As more effective diagnostic tools become available, the number of cases is expected to rise, and a recent study predicts that there will be 70 million people with glaucoma in 2020. 1 Glaucoma is considered to be a group of diseases characterized by progressive optic nerve degeneration that results in visual field loss and irreversible blindness. The cause of glaucoma is unknown, but several risk factors have been identified, including high intraocular pressure, age and genetic predisposition. Open angle and angle-closure glaucoma, the most common forms of the disease, are often associated with high intraocular pressure. A crucial element in the pathophysiology of all forms of glaucoma is the death of retinal ganglion cells (RGCs; Figure 1) and, as these are central nervous system neurons, their loss is irreversible. At present, there is no cure for glaucoma, and the standard treatment is to lower intraocular pressure by medication or surgery. However, a significant proportion of patients continue to experience visual loss even when pharmacological treatments effectively reduce eye pressure. Therefore, novel therapeutic approaches are needed for its treatment and management.Early-onset glaucoma, comprising primary congenital glaucoma and juvenile open-angle glaucoma, has a clear genetic basis. Between 10 and 30% of individuals with juvenile open-angle glaucoma have mutations in the gene encoding myocilin, 2,3 and, on average, B40% of people with primary congenital glaucoma have mutations in the gene encoding cytochrome P450 protein. 4 Both genes are expressed in the trabecular meshwork and ciliary body, and defects in these genes may cause ocular hypertension. The elucidation of the genetic basis underlying adult-onset glaucoma is difficult because the late onset of disease limits the number of individuals available for linkage analysis. However, at least 29 genetic loci for various forms of glaucoma and 12...

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Excitotoxic Death of Retinal NeuronsIn VivoOccurs via a Non-Cell-Autonomous Mechanism

Cited by 165 publications

References 98 publications

ProNGF induces TNFα-dependent death of retinal ganglion cells through a p75 ^NTR non-cell-autonomous signaling pathway

ProNGF induces TNFα-dependent death of retinal ganglion cells through a p75 ^NTR non-cell-autonomous signaling pathway

Glucocorticoid receptors in the retina, Müller glia and the formation of Müller glia-derived progenitors

Gene therapy for retinal ganglion cell neuroprotection in glaucoma

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Excitotoxic Death of Retinal NeuronsIn VivoOccurs via a Non-Cell-Autonomous Mechanism

Cited by 165 publications

References 98 publications

ProNGF induces TNFα-dependent death of retinal ganglion cells through a p75 NTR non-cell-autonomous signaling pathway

ProNGF induces TNFα-dependent death of retinal ganglion cells through a p75 NTR non-cell-autonomous signaling pathway

Glucocorticoid receptors in the retina, Müller glia and the formation of Müller glia-derived progenitors

Gene therapy for retinal ganglion cell neuroprotection in glaucoma

Contact Info

Product

Resources

About

ProNGF induces TNFα-dependent death of retinal ganglion cells through a p75 ^NTR non-cell-autonomous signaling pathway

ProNGF induces TNFα-dependent death of retinal ganglion cells through a p75 ^NTR non-cell-autonomous signaling pathway