Type-2 alkenes mediate synaptotoxicity in neurodegenerative diseases

Richard M. LoPachin, Terrence Gavin, David S. Barber

Research output: Contribution to journalReview article

32 Scopus citations

Abstract

Synaptic dysfunction appears to be an early pathogenic event in Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's disease. Although the molecular mechanism of this synaptotoxicity is not known, evidence suggests that these diseases are characterized by a common pathophysiological cascade involving oxidative stress, lipid peroxidation and the subsequent liberation of α,β-unsaturated carbonyl derivatives such as acrolein and 4-hydroxy-2-nonenal (HNE). A diverse body of in vivo and in vitro data have shown that these soft electrophilic chemicals can cause nerve terminal damage by forming Michael-type adducts with nucleophilic sulfhydryl groups on presynaptic proteins. Therefore, the endogenous generation of acrolein and HNE in oxidatively stressed neurons of certain brain regions might be mechanistically related to the synaptotoxicity associated with neurodegenerative conditions. In addition, acrolein and HNE are members of a large class of structurally related chemicals known as the type-2 alkenes. Chemicals in this class (e.g., acrylamide, methylvinyl ketone, and methyl acrylate) are pervasive pollutants in human environments and new research has shown that these α,β-unsaturated carbonyl derivatives are also toxic to nerve terminals. In this review, we provide evidence that the regional synaptotoxicity, which develops during the early stages of many neurodegenerative diseases, is mediated by endogenous generation of acrolein and HNE. Based on a presumed common nerve terminal site of action, we propose that the onset and progression of this neuropathogenic process is accelerated by environmental exposure to other type-2 alkenes.

Original languageEnglish (US)
Pages (from-to)871-882
Number of pages12
JournalNeurotoxicology
Volume29
Issue number5
DOIs
Publication statusPublished - Sep 1 2008

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Keywords

  • 4-Hydroxy-2-nonenal
  • Acrolein
  • Acrylamide
  • Alzheimer's disease
  • Amyotrophic lateral sclerosis
  • Oxidative injury
  • Parkinson's disease
  • Synapse

ASJC Scopus subject areas

  • Neuroscience(all)
  • Toxicology

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