Expression of the low affinity neurotrophin receptor p75 in spinal motoneurons in a transgenic mouse model for amyotrophic lateral sclerosis

Copray, J.C.V.M.; Jaarsma, Dick; Kst, B.M; Bruggeman, R; Mantingh, I.; Brouwer, Nieske; Boddeke, H. W. G. M.

doi:10.1016/s0306-4522(02)00755-8

Cited by 51 publications

(31 citation statements)

References 51 publications

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“…3B; 24 axons, n = 3). The p75 NTR receptor is not expressed in healthy MNs in adult mice (34), thus implying that this antibody was transported only in sensory axons. This p75 NTR antibody therefore represents a useful tool to selectively assess defects in axonal trafficking in sensory neurons in vivo.…”

Section: Resultsmentioning

confidence: 97%

Deficits in axonal transport precede ALS symptoms in vivo

Bilsland¹,

Sahai

Kelly

et al. 2010

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

359

343

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ALS is a fatal neurodegenerative disease characterized by selective motor neuron death resulting in muscle paralysis. Mutations in superoxide dismutase 1 (SOD1) are responsible for a subset of familial cases of ALS. Although evidence from transgenic mice expressing human mutant SOD1 G93A suggests that axonal transport defects may contribute to ALS pathogenesis, our understanding of how these relate to disease progression remains unclear. Using an in vivo assay that allows the characterization of axonal transport in single axons in the intact sciatic nerve, we have identified clear axonal transport deficits in presymptomatic mutant mice. An impairment of axonal retrograde transport may therefore represent one of the earliest axonal pathologies in SOD1 G93A mice, which worsens at an early symptomatic stage. A deficit in axonal transport may therefore be a key pathogenic event in ALS and an early disease indicator of motor neuron degeneration.

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Section: Resultsmentioning

confidence: 97%

Deficits in axonal transport precede ALS symptoms in vivo

Bilsland¹,

Sahai

Kelly

et al. 2010

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

359

343

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“…NTR has been implicated in motor neuron death occurring in transgenic mice overexpressing mutant Cu-Zn superoxide dismutase (SOD1) (Lowry et al, 2001b;Copray et al, 2003;Kust et al, 2003;Turner et al, 2003a,b) or after axotomy (Ferri et al, 1998;Wiese et al, 1999;Lowry et al, 2001a). Pure motor neuron cultures expressing p75 NTR are sensitive to NGF-induced apoptosis only when physiological concentrations of exogenous nitric oxide ( ⅐ NO) are present, either from a ⅐ NO donor or generated by feeder astrocyte monolayers (Pehar et al, 2004).…”

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.

114

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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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Expression of the low affinity neurotrophin receptor p75 in spinal motoneurons in a transgenic mouse model for amyotrophic lateral sclerosis

Cited by 51 publications

References 51 publications

Deficits in axonal transport precede ALS symptoms in vivo

Deficits in axonal transport precede ALS symptoms in vivo

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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