Interaction of Survival and Death Signaling in Basal Forebrain Neurons: Roles of Neurotrophins and Proneurotrophins

Volosin, Márta; Song, Wenyu; Almeida, Ramiro D.; Kaplan, David R.; Hempstead, Barbara L.; Friedman, Wilma J.

doi:10.1523/jneurosci.1560-06.2006

Cited by 240 publications

(222 citation statements)

References 59 publications

(96 reference statements)

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“…The role of p75 NTR as an apoptotic receptor is well established as it has been shown to facilitate developmental cell death of peripheral sympathetic neurons and early retinal neurons (8,(24)(25)(26). p75 NTR has also been implicated in cell loss following various forms of CNS injury and promotes apoptosis of cortical and hippocampal neurons, basal forebrain neurons, oligodendrocytes, and photoreceptor cells (8,(27)(28)(29)(30)(31). Overall, the functional role of p75 NTR in neuronal death is best understood in neurons that endogenously express this receptor.…”

Section: Resultsmentioning

confidence: 99%

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.

111

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: 99%

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.

111

100

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“…Recent studies have shown that proneurotrophins binding to p75 mediates cell death after injury or neurodegenerative diseases such as Alzheimer's dementia (Harrington et al 2004;Peng et al 2004;Pedraza et al 2005;Volosin et al 2006). Pro-neurotrophins are produced and then cleaved by furin and other proteases to produce the mature neurotrophin (Lee et al 2001).…”

Section: Introductionmentioning

confidence: 99%

“…Pro-neurotrophins are produced and then cleaved by furin and other proteases to produce the mature neurotrophin (Lee et al 2001). The precursor form of NGF, proNGF is responsible for inducing apoptotic death in particular cellular contexts (Lee et al 2001;Beattie et al 2002;Harrington et al 2004;Volosin et al 2006). Proneurotrophins, such as proNGF and proBDNF, preferentially interact with sortilin together with p75 to form a complex capable of activating an apoptotic cascade (Lee et al 2001;Nykjaer et al 2004;Teng et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Pro-NGF secreted by astrocytes promotes motor neuron cell death

Domeniconi

Hempstead

Chao

2007

Molecular and Cellular Neuroscience

109

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It is well established that motor neurons depend for their survival on many trophic factors. In this study, we show that the precursor form of NGF (proNGF) can induce the death of motor neurons via engagement of the p75 neurotrophin receptor. The pro-apoptotic activity was dependent upon the presence of sortilin, a p75 co-receptor expressed on motor neurons. One potential source of proNGF is reactive astrocytes, which upregulate the levels of proNGF in response to peroxynitrite, an oxidant and producer of free radicals. Indeed, motor neuron viability was sensitive to conditioned media from cultured astrocytes treated with peroxynitrite and this effect could be reversed using a specific antibody against the pro-domain of proNGF. These results are consistent with a role for activated astrocytes and proNGF in the induction of motor neuron death and suggest a possible therapeutic target for the treatment of motor neuron disease.

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“…Earlier studies in peripheral neurons have established a positive effect of p75 NTR on neurotrophin binding to Trk receptors, enhancing both ligand affinity and selectivity, and thereby strengthening survival responses (Lee et al, 1994;Rydén et al, 1997). In basal forebrain cholinergic neurons, however, simultaneous engagement of p75 NTR and Trk receptors through concomitant stimulation with pro-and mature neurotrophin ligands resulted in death, not survival, of these neurons (Volosin et al, 2006), indicating that p75 NTR signaling was dominant in this case. It would be interesting to test whether pro-neurotrophins can kill peripheral neurons in the absence or presence of their mature counterparts.…”

Section: Multisubunit Receptor Complexes For Neurotrophic Factorsmentioning

confidence: 99%

Assembly and activation of neurotrophic factor receptor complexes

Simi

Ibáñez

2010

Developmental Neurobiology

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Neurotrophic factors play important roles in the development and function of both neuronal and glial elements of the central and peripheral nervous systems. Their functional diversity is in part based on their ability to interact with alternative complexes of receptor molecules. This review focuses on our current understanding of the mechanisms that govern the assembly and activation of neurotrophic factor receptor complexes. The realization that many, if not the majority, of these complexes exist in a preassembled form at the plasma membrane has forced the revision of classical ligand-mediated oligomerization models, and led to the discovery of novel mechanisms of receptor activation and generation of signaling diversity which are likely to be shared by many different classes of receptors. ' 2010 Wiley Periodicals, Inc. Develop Neurobiol 70: 323-331, 2010

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Interaction of Survival and Death Signaling in Basal Forebrain Neurons: Roles of Neurotrophins and Proneurotrophins

Cited by 240 publications

References 59 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

Pro-NGF secreted by astrocytes promotes motor neuron cell death

Assembly and activation of neurotrophic factor receptor complexes

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Interaction of Survival and Death Signaling in Basal Forebrain Neurons: Roles of Neurotrophins and Proneurotrophins

Cited by 240 publications

References 59 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

Pro-NGF secreted by astrocytes promotes motor neuron cell death

Assembly and activation of neurotrophic factor receptor complexes

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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