Inhibition of p75NTR in glia potentiates TrkA-mediated survival of injured retinal ganglion cells

Lebrun-Julien, Frédéric; Morquette, Barbara; Douillette, Annie; Saragovi, H. Uri; Polo, Adriana Di

doi:10.1016/j.mcn.2008.12.005

Cited by 92 publications

(80 citation statements)

References 64 publications

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“…Immunostaining for TGF-␤2 in retinal ganglion cells and neurons of the INL was observed in E18.5 mouse embryos (Ma et al, 2007). Programmed cell death is detectable in the mouse retina from E12.5 to ϳ3 weeks after birth (Young, 1984;Farah and Easter, 2005), and it appears reasonable to assume that during most of this period, retinal TGF-␤ signaling is available at high activity levels to attenuate the apoptosis of retinal progenitor cells and of more differentiated retinal neurons in an autocrine-or paracrine-dependent manner.…”

Section: Discussionmentioning

confidence: 98%

“…In this period, the precursors of retinal ganglion cells and neurons in the INL proliferate (Sidman, 1961;Farah and Easter, 2005), which are reduced in number in the adult Tgfbr2 ⌬oc mice in our study. TrkA is also expressed in differentiated retinal ganglion cells (Lebrun-Julien et al, 2009) and may mediate the protective effects of TGF-␤/ NGF on the apoptosis of retinal ganglion cells in mouse pups during synaptogenesis.…”

Section: Tgfb1mentioning

confidence: 99%

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TGF- Signaling Protects Retinal Neurons from Programmed Cell Death during the Development of the Mammalian Eye

Braunger

Pielmeier

Demmer

et al. 2013

Journal of Neuroscience

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We investigated the influence of transforming growth factor-␤ (TGF-␤) signaling on developmental programmed cell death in the mouse retina by direct and specific molecular targeting of TGF-␤ type II receptor (T␤RII) and Smad7 in retinal progenitor cells. Mice were generated carrying a conditional deletion of the T␤RII in cells that originate from the inner layer of the optic cup. The animals showed a significant decrease of phosphorylated Smad3 in both the central and peripheral retina, which indicates the diminished activity of TGF-␤ signaling. T␤RII deficiency significantly increased the apoptotic death of retinal neurons during embryonic and postnatal development without affecting their proliferation. In contrast, treatment with TGF-␤2 inhibited cell death of retinal ganglion cells in dissociated retinal cell cultures, an effect that was blocked by inhibiting the phosphorylation of Smad3. The increase in apoptosis during development resulted in a significant reduction in the number of neurons in adult T␤RII-deficient mice. The effect was most pronounced in the inner retina neurons and resulted in functional deficits as determined by electroretinography. In contrast, a conditional deletion of TGF-␤-inhibiting Smad7 in retinal neurons significantly enhanced Smad3 phosphorylation and significantly decreased apoptosis of retinal neurons in embryos and pups. Moreover, the number of retinal ganglion cells was significantly higher in Smad7-deficient mice compared with control littermates. T␤RII-deficient pups showed a lower level of nerve growth factor (NGF) in its mRNA; however, higher levels were observed in Smad7-deficient pups, which strongly suggests that the protective effects of TGF-␤ signaling on developmental cell death are mediated through NGF.

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Section: Discussionmentioning

confidence: 98%

Section: Tgfb1mentioning

confidence: 99%

TGF- Signaling Protects Retinal Neurons from Programmed Cell Death during the Development of the Mammalian Eye

Braunger

Pielmeier

Demmer

et al. 2013

Journal of Neuroscience

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“…109 The Nogo receptor (NgR) serves as a high-affinity receptor for Nogo-A, myelin-associated glycoprotein and oligodendrocyte-myelin glycoprotein, and has two partners responsible for signal transduction: p75 NTR and the NgR-interacting protein (LINGO-1). 109 Adult RGCs do not express p75 NTR , 110 and a newly identified co-receptor, named TROY, has been shown to interact with NgR and LINGO-1 to promote growth inhibition in these neurons. 111 The strategy to block NgR has received attention because it offers a single target to neutralize signaling via Nogo, myelin-associated glycoprotein or oligodendrocyte-myelin glycoprotein.…”

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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“…p75 increased production of neurotoxic proteins TNF-α and α(2)-macroglobulin. p75 was found to be expressed by the majority of glia and Muller cells and TrkA was found mainly in RGCs (Lebrun-Julien et al, 2009). In another study, wild type NGF failed to protect RGCs in tested models of glaucoma and nerve axotomy.…”

Section: Neuroprotection Via Nt Receptors And/or Their Downstream Sigmentioning

confidence: 92%

“…However the best results were obtained by a combination of a TrkA receptor agonist together with a pressure lowering drug (betaxolol) in which 90% reduction of RGCs loss was observed (Shi et al, 2007). The synergistic effect of a combination of NGF and peptidomimetic TrkA agonist, along with a peptidomimetic p75 antagonist prevented RGC cells loss following optic nerve transection (Lebrun-Julien et al, 2009). p75 increased production of neurotoxic proteins TNF-α and α(2)-macroglobulin.…”

Section: Neuroprotection Via Nt Receptors And/or Their Downstream Sigmentioning

confidence: 99%

Neuroprotection in Glaucoma

Mueller¹,

Stankowska²,

Krishnamoorthy³

2011

Glaucoma - Basic and Clinical Concepts

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Inhibition of p75NTR in glia potentiates TrkA-mediated survival of injured retinal ganglion cells

Cited by 92 publications

References 64 publications

TGF- Signaling Protects Retinal Neurons from Programmed Cell Death during the Development of the Mammalian Eye

TGF- Signaling Protects Retinal Neurons from Programmed Cell Death during the Development of the Mammalian Eye

Gene therapy for retinal ganglion cell neuroprotection in glaucoma

Neuroprotection in Glaucoma

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