Spinal cord motoneurons express p75NGFR and p145trkB mRNA in amyotrophic lateral sclerosis

Seeburger, Jeffrey L.; Tarras, Seth; Natter, Howard M.; Springer, Joe E.

doi:10.1016/0006-8993(93)90304-6

Cited by 87 publications

(64 citation statements)

References 23 publications

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“…During development and following injury, the p75 neurotrophin receptor ( p75 NTR ; also known as NGFR) has been shown to mediate motor neuron death (Seeburger et al, 1993;Lowry et al, 2001;Dechant and Barde, 2002;Ibanez and Simi, 2012) in response to nerve growth factor (NGF) (Sedel et al, 1999;Ernfors, 2001) or its immature precursor ( proNGF), released by activated astrocytes (Pehar et al, 2004;Domeniconi et al, 2006). However,p75 NTR is a multifunctional receptor for both mature and pro-neurotrophins, capable of regulating different biological effects in response to its ligands (Roux and Barker, 2002;Blochl and Blochl, 2007;.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of motor neuron death in vitro and in vivo by a p75 neurotrophin receptor intracellular domain fragment

Matusica

Alfonsi

Turner

et al. 2016

Journal of Cell Science

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The p75 neurotrophin receptor ( p75 NTR ; also known as NGFR) can mediate neuronal apoptosis in disease or following trauma, and facilitate survival through interactions with Trk receptors. Here we tested the ability of a p75NTR -derived trophic cell-permeable peptide, c29, to inhibit p75 NTR -mediated motor neuron death. Acute c29 application to axotomized motor neuron axons decreased cell death, and systemic c29 treatment of SOD1 G93A mice, a common model of amyotrophic lateral sclerosis, resulted in increased spinal motor neuron survival mid-disease as well as delayed disease onset. Coincident with this, c29 treatment of these mice reduced the production of p75 NTR cleavage products. Although c29 treatment inhibited mature-and pro-nerve-growth-factor-induced death of cultured motor neurons, and these ligands induced the cleavage of p75 NTR in motor-neuron-like NSC-34 cells, there was no direct effect of c29 on p75 NTR cleavage. Rather, c29 promoted motor neuron survival in vitro by enhancing the activation of TrkB-dependent signaling pathways, provided that low levels of brain-derived neurotrophic factor (BDNF) were present, an effect that was replicated in vivo in SOD1 G93A mice. We conclude that the c29 peptide facilitates BDNF-dependent survival of motor neurons in vitro and in vivo.

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Section: Introductionmentioning

confidence: 99%

Inhibition of motor neuron death in vitro and in vivo by a p75 neurotrophin receptor intracellular domain fragment

Matusica

Alfonsi

Turner

et al. 2016

Journal of Cell Science

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“…However, adult motor neurons can reexpress p75 NTR after nerve injury (Koliatsos et al, 1991;Rende et al, 1995;Ferri et al, 1998) and in amyotrophic lateral sclerosis (ALS) (Seeburger et al, 1993;Lowry et al, 2001b). Induction of p75 NTR renders motor neurons vulnerable to NGF-induced apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Superoxide Production and Nuclear Factor Erythroid 2-Related Factor 2 Activation in p75 Neurotrophin Receptor-Induced Motor Neuron Apoptosis

Pehar

Vargas²,

Robinson³

et al. 2007

J. Neurosci.

115

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Nerve growth factor (NGF) can induce apoptosis by signaling through the p75 neurotrophin receptor (p75 NTR ) in several nerve cell populations. Cultured embryonic motor neurons expressing p75 NTR are not vulnerable to NGF unless they are exposed to an exogenous flux of nitric oxide ( ⅐ NO). In the present study, we show that p75 NTR -mediated apoptosis in motor neurons involved neutral sphingomyelinase activation, increased mitochondrial superoxide production, and cytochrome c release to the cytosol. The mitochondria-targeted antioxidants mitoQ and mitoCP prevented neuronal loss, further evidencing the role of mitochondria in NGF-induced apoptosis. In motor neurons overexpressing the amyotrophic lateral sclerosis (ALS)-linked superoxide dismutase 1 G93A (SOD1 G93A ) mutation, NGF induced apoptosis even in the absence of an external source of ⅐ NO. The increased susceptibility of SOD1 G93A motor neurons to NGF was associated to decreased nuclear factor erythroid 2-related factor 2 (Nrf2) expression and downregulation of the enzymes involved in glutathione biosynthesis. In agreement, depletion of glutathione in nontransgenic motor neurons reproduced the effect of SOD1 G93A expression, increasing their sensitivity to NGF. In contrast, rising antioxidant defenses by Nrf2 activation prevented NGF-induced apoptosis. Together, our data indicate that p75 NTR -mediated motor neuron apoptosis involves ceramide-dependent increased mitochondrial superoxide production. This apoptotic pathway is facilitated by the expression of ALS-linked SOD1 mutations and critically modulated by Nrf2 activity.

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“…In amyotrophic lateral sclerosis, p75 immuno-reactivity is increased in spinal motor neurons (Seeburger et al 1993;Copray et al 2003) while both TrkA and TkB are absent (Seeburger et al 1993). In a mouse model of the disease, the onset of degeneration was delayed in p75-null female mice (Kust et al 2003) and antisense-mediated knockdown of p75 in adult animals delayed disease progression (Turner et al 2003).…”

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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Spinal cord motoneurons express p75NGFR and p145trkB mRNA in amyotrophic lateral sclerosis

Cited by 87 publications

References 23 publications

Inhibition of motor neuron death in vitro and in vivo by a p75 neurotrophin receptor intracellular domain fragment

Inhibition of motor neuron death in vitro and in vivo by a p75 neurotrophin receptor intracellular domain fragment

Mitochondrial Superoxide Production and Nuclear Factor Erythroid 2-Related Factor 2 Activation in p75 Neurotrophin Receptor-Induced Motor Neuron Apoptosis

Pro-NGF secreted by astrocytes promotes motor neuron cell death

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