Astrocytic production of nerve growth factor in motor neuron apoptosis: Implications for amyotrophic lateral sclerosis

Mariana Pehar, Patricia Cassina, Marcelo R. Vargas, Raquel Castellanos, Liliana Viera, Joseph S. Beckman, Alvaro G. Estévez, Luis Barbeito

Resultado de la investigación: Article

155 Citas (Scopus)

Resumen

Reactive astrocytes frequently surround degenerating motor neurons in patients and transgenic animal models of amyotrophic lateral sclerosis (ALS). We report here that reactive astrocytes in the ventral spinal cord of transgenic ALS-mutant G93A superoxide dismutase (SOD) mice expressed nerve growth factor (NGF) in regions where degenerating motor neurons expressed p75 neurotrophin receptor (p75NTR) and were immunoreactive for nitrotyrosine. Cultured spinal cord astrocytes incubated with lipopolysaccharide (LPS) or peroxynitrite became reactive and accumulated NGF in the culture medium. Reactive astrocytes caused apoptosis of embryonic rat motor neurons plated on the top of the monolayer. Such motor neuron apoptosis could be prevented when either NGF or p75NTR was inhibited with blocking antibodies. In addition, nitric oxide synthase inhibitors were also protective. Exogenous NGF stimulated motor neuron apoptosis only in the presence of a low steady state concentration of nitric oxide. NGF induced apoptosis in motor neurons from p75NTR +/+ mouse embryos but had no effect in p75NTR-/- knockout embryos. Culture media from reactive astrocytes as well as spinal cord lysates from symptomatic G93A SOD mice-stimulated motor neuron apoptosis, but only when incubated with exogenous nitric oxide. This effect was prevented by either NGF or p75NTR blocking-antibodies suggesting that it might be mediated by NGF and/or its precursor forms. Our findings show that NGF secreted by reactive astrocytes induce the death of p75-expressing motor neurons by a mechanism involving nitric oxide and peroxynitrite formation. Thus, reactive astrocytes might contribute to the progressive motor neuron degeneration characterizing ALS.

Idioma originalEnglish
Páginas (desde-hasta)464-473
Número de páginas10
PublicaciónJournal of Neurochemistry
Volumen89
N.º2
DOI
EstadoPublished - 1 abr 2004

Huella dactilar

Amyotrophic Lateral Sclerosis
Motor Neurons
Nerve Growth Factor
Neurons
Astrocytes
Apoptosis
Nerve Growth Factor Receptor
Spinal Cord
Nitric Oxide
Peroxynitrous Acid
Blocking Antibodies
Superoxide Dismutase
Culture Media
Embryonic Structures
Nerve Degeneration
Genetically Modified Animals
Nitric Oxide Synthase
Lipopolysaccharides
Rats
Monolayers

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Citar esto

Pehar, M., Cassina, P., Vargas, M. R., Castellanos, R., Viera, L., Beckman, J. S., ... Barbeito, L. (2004). Astrocytic production of nerve growth factor in motor neuron apoptosis: Implications for amyotrophic lateral sclerosis. Journal of Neurochemistry, 89(2), 464-473. https://doi.org/10.1111/j.1471-4159.2004.02357.x
Pehar, Mariana ; Cassina, Patricia ; Vargas, Marcelo R. ; Castellanos, Raquel ; Viera, Liliana ; Beckman, Joseph S. ; Estévez, Alvaro G. ; Barbeito, Luis. / Astrocytic production of nerve growth factor in motor neuron apoptosis : Implications for amyotrophic lateral sclerosis. En: Journal of Neurochemistry. 2004 ; Vol. 89, N.º 2. pp. 464-473.
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abstract = "Reactive astrocytes frequently surround degenerating motor neurons in patients and transgenic animal models of amyotrophic lateral sclerosis (ALS). We report here that reactive astrocytes in the ventral spinal cord of transgenic ALS-mutant G93A superoxide dismutase (SOD) mice expressed nerve growth factor (NGF) in regions where degenerating motor neurons expressed p75 neurotrophin receptor (p75NTR) and were immunoreactive for nitrotyrosine. Cultured spinal cord astrocytes incubated with lipopolysaccharide (LPS) or peroxynitrite became reactive and accumulated NGF in the culture medium. Reactive astrocytes caused apoptosis of embryonic rat motor neurons plated on the top of the monolayer. Such motor neuron apoptosis could be prevented when either NGF or p75NTR was inhibited with blocking antibodies. In addition, nitric oxide synthase inhibitors were also protective. Exogenous NGF stimulated motor neuron apoptosis only in the presence of a low steady state concentration of nitric oxide. NGF induced apoptosis in motor neurons from p75NTR +/+ mouse embryos but had no effect in p75NTR-/- knockout embryos. Culture media from reactive astrocytes as well as spinal cord lysates from symptomatic G93A SOD mice-stimulated motor neuron apoptosis, but only when incubated with exogenous nitric oxide. This effect was prevented by either NGF or p75NTR blocking-antibodies suggesting that it might be mediated by NGF and/or its precursor forms. Our findings show that NGF secreted by reactive astrocytes induce the death of p75-expressing motor neurons by a mechanism involving nitric oxide and peroxynitrite formation. Thus, reactive astrocytes might contribute to the progressive motor neuron degeneration characterizing ALS.",
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Pehar, M, Cassina, P, Vargas, MR, Castellanos, R, Viera, L, Beckman, JS, Estévez, AG & Barbeito, L 2004, 'Astrocytic production of nerve growth factor in motor neuron apoptosis: Implications for amyotrophic lateral sclerosis', Journal of Neurochemistry, vol. 89, n.º 2, pp. 464-473. https://doi.org/10.1111/j.1471-4159.2004.02357.x

Astrocytic production of nerve growth factor in motor neuron apoptosis : Implications for amyotrophic lateral sclerosis. / Pehar, Mariana; Cassina, Patricia; Vargas, Marcelo R.; Castellanos, Raquel; Viera, Liliana; Beckman, Joseph S.; Estévez, Alvaro G.; Barbeito, Luis.

En: Journal of Neurochemistry, Vol. 89, N.º 2, 01.04.2004, p. 464-473.

Resultado de la investigación: Article

TY - JOUR

T1 - Astrocytic production of nerve growth factor in motor neuron apoptosis

T2 - Implications for amyotrophic lateral sclerosis

AU - Pehar, Mariana

AU - Cassina, Patricia

AU - Vargas, Marcelo R.

AU - Castellanos, Raquel

AU - Viera, Liliana

AU - Beckman, Joseph S.

AU - Estévez, Alvaro G.

AU - Barbeito, Luis

PY - 2004/4/1

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N2 - Reactive astrocytes frequently surround degenerating motor neurons in patients and transgenic animal models of amyotrophic lateral sclerosis (ALS). We report here that reactive astrocytes in the ventral spinal cord of transgenic ALS-mutant G93A superoxide dismutase (SOD) mice expressed nerve growth factor (NGF) in regions where degenerating motor neurons expressed p75 neurotrophin receptor (p75NTR) and were immunoreactive for nitrotyrosine. Cultured spinal cord astrocytes incubated with lipopolysaccharide (LPS) or peroxynitrite became reactive and accumulated NGF in the culture medium. Reactive astrocytes caused apoptosis of embryonic rat motor neurons plated on the top of the monolayer. Such motor neuron apoptosis could be prevented when either NGF or p75NTR was inhibited with blocking antibodies. In addition, nitric oxide synthase inhibitors were also protective. Exogenous NGF stimulated motor neuron apoptosis only in the presence of a low steady state concentration of nitric oxide. NGF induced apoptosis in motor neurons from p75NTR +/+ mouse embryos but had no effect in p75NTR-/- knockout embryos. Culture media from reactive astrocytes as well as spinal cord lysates from symptomatic G93A SOD mice-stimulated motor neuron apoptosis, but only when incubated with exogenous nitric oxide. This effect was prevented by either NGF or p75NTR blocking-antibodies suggesting that it might be mediated by NGF and/or its precursor forms. Our findings show that NGF secreted by reactive astrocytes induce the death of p75-expressing motor neurons by a mechanism involving nitric oxide and peroxynitrite formation. Thus, reactive astrocytes might contribute to the progressive motor neuron degeneration characterizing ALS.

AB - Reactive astrocytes frequently surround degenerating motor neurons in patients and transgenic animal models of amyotrophic lateral sclerosis (ALS). We report here that reactive astrocytes in the ventral spinal cord of transgenic ALS-mutant G93A superoxide dismutase (SOD) mice expressed nerve growth factor (NGF) in regions where degenerating motor neurons expressed p75 neurotrophin receptor (p75NTR) and were immunoreactive for nitrotyrosine. Cultured spinal cord astrocytes incubated with lipopolysaccharide (LPS) or peroxynitrite became reactive and accumulated NGF in the culture medium. Reactive astrocytes caused apoptosis of embryonic rat motor neurons plated on the top of the monolayer. Such motor neuron apoptosis could be prevented when either NGF or p75NTR was inhibited with blocking antibodies. In addition, nitric oxide synthase inhibitors were also protective. Exogenous NGF stimulated motor neuron apoptosis only in the presence of a low steady state concentration of nitric oxide. NGF induced apoptosis in motor neurons from p75NTR +/+ mouse embryos but had no effect in p75NTR-/- knockout embryos. Culture media from reactive astrocytes as well as spinal cord lysates from symptomatic G93A SOD mice-stimulated motor neuron apoptosis, but only when incubated with exogenous nitric oxide. This effect was prevented by either NGF or p75NTR blocking-antibodies suggesting that it might be mediated by NGF and/or its precursor forms. Our findings show that NGF secreted by reactive astrocytes induce the death of p75-expressing motor neurons by a mechanism involving nitric oxide and peroxynitrite formation. Thus, reactive astrocytes might contribute to the progressive motor neuron degeneration characterizing ALS.

KW - Amyotrophic lateral sclerosis

KW - Astrocyte

KW - Motor neuron

KW - Nerve growth factor

KW - Nitric oxide

KW - P75 neurotrophin receptor

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