Mechanism of the neurotoxicity of MPTP. An update

Thomas P. Singer*, Rona R. Ramsay

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

189 Citations (Scopus)

Abstract

This review summarizes advances in our understanding of the biochemical events which underlie the remarkable neurotoxic action of MPTP (1-methyl-4-phenyl-1-1,2,3,6-tetrahydropyridine) and the parkinsonian symptoms it causes in primates. The initial biochemical event is a two-step oxidation by monoamine oxidase B in glial cells to MPP+ (1-methyl-4-phenylpyridinium). A large number of MPTP analogs substituted in the aromatic (but not in the pyridine) ring are also oxidized by monoamine oxidase A or B, is in some cases faster than any previously recognized substrate. Alkyl substitution at the 2'-position changes MPTP, a predominantly B type substrate, to an A substrate. Following concentration in the dopamine neurons by the synaptic system, which has a high affinity for the carrier, MPP+ and its positively charged neurotoxic analogs are further concentrated by the electrical gradient of the inner membrane and then more slowly penetrate the hydrophobic reaction site on NADH dehydrogenase. Both of the latter events are accelerated by the tetraphenylboron anion, which forms ion pairs with MPP+ and its analogs. Mitochondrial damage is now widely accepted as the primary cause of the MPTP induced death of the nigrostriatal cells. The molecular target of MPP+, its neurotoxic product, is NADH dehydrogenase. Recent experiments suggest that the binding site is at or near the combining site of the classical respiratory inhibitors, rotenone and piericidin A.

Original languageEnglish
Pages (from-to)1-8
Number of pages8
JournalFEBS Letters
Volume274
Issue number1-2
DOIs
Publication statusPublished - 12 Nov 1990

Keywords

  • Monoamine oxidase
  • MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)
  • NADH dehydrogenase
  • Neurotoxin

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