Endothelial nitric oxide synthase overexpression by neuronal cells in neurodegeneration: A link between inflammation and neuroprotection

Clara De Palma, Sestina Falcone, Chris Panzeri, Sonia Radice, Maria Teresa Bassi, Emilio Clementi

Research output: Contribution to journalArticle

Abstract

The roles of neuronal and inducible nitric oxide synthases in neurones have been extensively investigated; by contrast, the biological significance of endothelial nitric oxide synthase (eNOS) overexpression that occurs in several pathological conditions has not yet been studied. We have started addressing this issue in a cell model of neurodegeneration, i.e. human SKNBE neuroblastoma cells transfected with a mutant form of alsin, a protein causing an early-onset type of amyotrophic lateral sclerosis, ALS2. We found that eNOS, which is endogenously expressed by these cells, was activated by tumour necrosis factor-α (TNF-α), a proinflammatory cytokine that plays important roles in ALS2 and several neurodegenerative diseases. The TNF-α-dependent eNOS activation occurred through generation, by sphingosine-kinase-1, of sphingosine-1-phosphate, stimulation of its membrane receptors and activation of Akt, as determined using small interference RNA and dominant negative constructs specific for the enzymes and receptors. eNOS activation by TNF-α conferred cytoprotection from excitotoxicity and neurotoxic cues such as reactive oxygen species, endoplasmic reticulum stress, DNA damage, and mutated alsin itself. Our results suggest that overexpression of eNOS by neurones is a broad-range protective mechanism activated during damage and establish a link of pathophysiological relevance between this enzyme and inflammation accompanying neurodegenerative diseases. These findings also question the concept that high NO output in the presence of oxidative stress leads always to peroxynitrite formation contributing to neurodegeneration.

Original languageEnglish
Pages (from-to)193-204
Number of pages12
JournalJournal of Neurochemistry
Volume106
Issue number1
DOIs
Publication statusPublished - Jul 2008

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Keywords

  • Alsin
  • Amyotrophic lateral sclerosis
  • Apoptosis
  • Endothelial nitric oxide synthase
  • Neurone
  • Tumour necrosis factor-α

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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