Peroxynitrite transforms nerve growth factor into an apoptotic factor for motor neurons

Autor: Joseph S. Beckman, Pedro M. Alzari, Kristine M. Robinson, Patrick England, Patricia Cassina, Luis Barbeito, Mariana Pehar, Marcelo R. Vargas
Přispěvatelé: Instituto de Investigaciones Biológicas Clemente Estable [Montevideo] (IIBCE), Oregon State University (OSU), Universidad de la República (UDELAR), Biochimie et Biophysique des Macromolécules, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Biochimie Structurale, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], This work was supported by NIH Grants FIRCA RO3TW006482 and AT002034 to J.S.B and L.B, additional support was provided by PEDECIBA and the Linus Pauling Institute. This work made use of the Cell Imaging and Mass Spectrometry Core Facilities of the Environmental Health Sciences Center (ES00210) sponsored by the National Institute of Environmental Health Sciences., Universidad de la República [Montevideo] (UDELAR), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Rok vydání: 2006
Předmět:
Free radicals
Apoptosis
Electrophoretic Mobility Shift Assay
Receptor
Nerve Growth Factor
Biochemistry
Peroxynitrite
Mass Spectrometry
MESH: Tyrosine
MESH: Reactive Nitrogen Species
chemistry.chemical_compound
MESH: Oligonucleotides
Antisense
0302 clinical medicine
Nerve Growth Factor
Glial cell line-derived neurotrophic factor
MESH: Animals
MESH: Nerve Growth Factor
Cells
Cultured
MESH: Peroxynitrous Acid
NGF
Motor Neurons
0303 health sciences
[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Structural Biology [q-bio.BM]
biology
Chemistry
Nitrotyrosine
MESH: Reactive Oxygen Species
Reactive Nitrogen Species
Cell biology
medicine.anatomical_structure
MESH: Motor Neurons
MESH: Cells
Cultured
Neurotrophin
MESH: Rats
[PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph]
Blotting
Western
[SDV.BC]Life Sciences [q-bio]/Cellular Biology
Nitric oxide
p75NTR
03 medical and health sciences
Downregulation and upregulation
Peroxynitrous Acid
Physiology (medical)
[CHIM.CRIS]Chemical Sciences/Cristallography
medicine
MESH: Blotting
Western
Animals
[SDV.BBM]Life Sciences [q-bio]/Biochemistry
Molecular Biology
030304 developmental biology
MESH: Mass Spectrometry
MESH: Apoptosis
MESH: Receptor
Nerve Growth Factor
Oligonucleotides
Antisense
Motor neuron
Rats
Nerve growth factor
nervous system
MESH: Electrophoretic Mobility Shift Assay
biology.protein
Tyrosine
[INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM]
Reactive Oxygen Species
030217 neurology & neurosurgery
Zdroj: Free Radical Biology and Medicine
Free Radical Biology and Medicine, Elsevier, 2006, 41 (11), pp.1632-1644. ⟨10.1016/j.freeradbiomed.2006.08.010⟩
Free Radical Biology and Medicine, 2006, 41 (11), pp.1632-1644. ⟨10.1016/j.freeradbiomed.2006.08.010⟩
ISSN: 0891-5849
DOI: 10.1016/j.freeradbiomed.2006.08.010
Popis: International audience; Nerve growth factor (NGF) overexpression and increased production of peroxynitrite occur in several neurodegenerative diseases. We investigated whether NGF could undergo posttranslational oxidative or nitrative modifications that would modulate its biological activity. Compared to native NGF, peroxynitrite-treated NGF showed an exceptional ability to induce p75(NTR)-dependent motor neuron apoptosis at physiologically relevant concentrations. Whereas native NGF requires an external source of nitric oxide (NO) to induce motor neuron death, peroxynitrite-treated NGF induced motor neuron apoptosis in the absence of exogenous NO. Nevertheless, NO potentiated the apoptotic activity of peroxynitrite-modified NGF. Blocking antibodies to p75(NTR) or downregulation of p75(NTR) expression by antisense treatment prevented motor neuron apoptosis induced by peroxynitrite-treated NGF. We investigated what oxidative modifications were responsible for inducing a toxic gain of function and found that peroxynitrite induced tyrosine nitration in a dose-dependent manner. Moreover, peroxynitrite triggered the formation of stable high-molecular-weight oligomers of NGF. Preventing tyrosine nitration by urate abolished the effect of peroxynitrite on NGF apoptotic activity. These results indicate that the oxidation of NGF by peroxynitrite enhances NGF apoptotic activity through p75(NTR) 10,000-fold. To our knowledge, this is the first known posttranslational modification that transforms a neurotrophin into an apoptotic agent.
Databáze: OpenAIRE
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