Advertisement

Biochemistry Of The Neurotoxic Action Of MPTP And What It May Teach Us About The Etiology Of Idiopathic Parkinsonism

  • Thomas P. Singer
  • Rona R. Ramsay
  • Kathleen A. McKeown
Chapter
  • 93 Downloads

Abstract

The past four years have been an exciting period in the history of parkinsonian research. Thanks to the efforts of an extraordinary number of investigators who have entered the field and a close interaction among neurologists, pharmacologists, biochemists, cell biologists, and chemists, we have progressed in a short time span from the first report that MPTP causes neurological symptoms close to those seen in Parkinsonism patients to an understanding of the main events leading to nigrostriatal cell death initiated by MPTP. One purpose of this paper is to summarize the biochemical events involved in this process, emphasizing recent, largely unpublished data and pointing out unresolved questions. Our second aim is to give an overview of what is being done to provide evidence for the hypothesis, which is gaining increasing acceptance, that idiopathic Parkinsonism is caused by slow-acting environmental neurotoxins. We will point out the battery of relatively simple in vitro tests for screening such potential neurotoxins and how they may eventually facilitate elimination of the disease. The original studies to be summarized represent, in part, collaboration with our colleagues, A. Trevor and N. Castagnoli at our University and in part, collaboration with Dr. R. Heikkila’s laboratory.

Keywords

NADH Dehydrogenase Idiopathic Parkinsonism Brain Mitochondrion NADH Oxidation Neurotoxic Action 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Chiba, K., Trevor, A. and Castagnoll, N., Jr. (1984). Metabolism of the neurotoxic testiary amine, MPTP, by brain monoamine oxidase. Biochem. Biophys. Res. Commun. 120: 574–578.PubMedCrossRefGoogle Scholar
  2. Salach, J.I., Singer, T.P., Castagnoli, N., Jr. and Trevor, A.J. (1984). Oxidation of the neurotoxic amine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by monoamine oxidases A and B and suicide inactivation of the enzymes by MPTP. Biochem. Biophys. Res. Commun. 125: 831–825.CrossRefGoogle Scholar
  3. Singer, T.P., Salach, J.I., Castagnoli, N., Jr. and Trevor, A. (1986). Interactions of the neurotoxic amine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine with monoamine oxidases. Biochem. J. 235: 785–789.PubMedGoogle Scholar
  4. Javitch, J.A., D’Amato, R.J., Strittmatter, S.M. and Snyder, S.H. (1985). Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity. Proc. Natl. Acad. Sci. 82: 2173–2177.PubMedCrossRefGoogle Scholar
  5. Nicklas, W.J., Vyas, I. andHeikkila, R.E. (1985). Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenylpyridinium, a metabolite of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Life Sci. 36: 2503–2508.PubMedCrossRefGoogle Scholar
  6. Ramsay, R.R., Dadgar, J., Trevor, A. and Singer, T.P. (1987). Energy-driven uptake of N-methyl-4-phenyl-pyridine by brain mitochondria mediates the neurotoxicity of MPTP. Life Sci. 39: 581–588.CrossRefGoogle Scholar
  7. Ramsay, R.R. and Singer, T.P. (1986). Energy-dependent uptake of N-methyl-4-phenylpyridinium, the neurotoxic, metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydiopyridine, by mitochondria. J. Biol. Chem. 261: 7585–7587.PubMedGoogle Scholar
  8. Ramsay, R.R. Kowal, A.T., Johnson, M.K., Salach, J.I., and Singer, T.P. (1987). The inhibition site of MPP+, the neurotoxic bioactivation product of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine is near the Q-binding site of NADH dehydrogenase. Arch. Biochim. Biophys. 259: 645–649.CrossRefGoogle Scholar
  9. Singer, T.P., Castagnoli N., Ramsay, R.R., and Trevor, A.J. (1987). Biochemical events in the development of parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. J. Neurochem. 49: 1–8.PubMedCrossRefGoogle Scholar
  10. Horgan, D.J., Singer, T.P. and Casida, J.E. (1968). Studies on the respiratory chain-linked reduced nicotinamide adenine dinucleotide dehydrogenase. XIII. Binding sites of rotenone, piericidin A, and amytal in the respiratory chain. J. Biol. Chem. 243: 834–841.PubMedGoogle Scholar
  11. Palmer, A., Horgan, D.J., Tisdale, H., Singer, T.P. and Beinert, H. (1968). Studies on the respiratory chain-linked reduced nicotinamide adenine dinucleotide dehydrogenase. XIV. Location of the sites of inhibition of rotenone, barbiturates, and piericidin by means of electron paramagnetic resonance spectroscopy. J. Biol. Chem. 243: 844–847.PubMedGoogle Scholar
  12. Youngster, S.K., Heikkila, R.E., McKeown, K.A., and Singer, T.P. (to be published)Google Scholar
  13. Youngster, S.K., Sonsalla, P.K. and Heikkila, R.E. (1987). Evaluation of the biological activity of several analogs of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. J. Neurochem. 48: 992–934.CrossRefGoogle Scholar
  14. Youngster, S.K., (1987). Ph.D. Thesis, New Jersey Medical College.Google Scholar
  15. Singer, T.P., Salach, J.I. and Crabtree, D. (1985). Reversible inhibition and mechanism-based irréversible in-activation of monoamine oxidases by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Biochem. Biophys. Res. Commun. 127: 707–712.PubMedCrossRefGoogle Scholar
  16. Sayre, L.M., Arora, P.K., Feka, S.C., andUrbach, F.L. (1986). Mechanism of induction of Parkinson’s Disease by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Chemical and electrochemical characterization of a geminal-dimethyl-blocked analogue of a postulated toxic metabolite. J. Am. Chem. Soc. 108: 2464–2466.PubMedCrossRefGoogle Scholar
  17. Christie-Pope, B., Burns, R.S. and Whetsell, W.O., Jr. (1987). Ultrastructural alterations induced by 1-methyl-4-phenylpyridine (MPP +) in organotypic cultures of canine substantia nigra and rat mesencephalon. Neurosci. Soc. Abstr., p.788.Google Scholar
  18. Sanchez-Ramos, J.R., Barrett, J.N., Goldstein, M, Weiner, W.J. andHefti, F. (1986). MPP+, but not MPTP is toxic to dopamine neurons in cultures of dissociated rat mesencephalic neurons. Neurosci. Lett. 72 215–220. Neurosci. Lett. 72 215–220.PubMedCrossRefGoogle Scholar
  19. Sanchez-Ramos, J.R. and Hefti, F., personal communicationGoogle Scholar
  20. Pressman, B.C. (1963). The effects of guanidine and alkylguanidines on the energy transfer reactions of mitochondria. J. Biol. Chem. 238: 401–409.Google Scholar
  21. Ramsay, R.R., McKeown, K.A., Johnson, E.A., Booth, R.G., and Singer, T.P. (1987). Inhibition of NADH oxidation by pyridine derivatives. Biochem. Biophys. Res. Commun. 146: 53–60.PubMedCrossRefGoogle Scholar
  22. Ramsay, R.R., Salach, J.I., Dadgar, J., and Singer, T.P. (1986). Inhibition of mitochondrial NADH dehydrogenase by pyridine derivatives and its possible relation to experimental and idiopathic parkinsonism. Biochem. Biophys. Res. Commun. 135 269–275PubMedCrossRefGoogle Scholar
  23. Snyder, S.H. and D’Amato, R.J. (1985). Predicting parkinson’s disease. Nature 317: 198–199PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New york 1988

Authors and Affiliations

  • Thomas P. Singer
    • 1
    • 2
  • Rona R. Ramsay
    • 1
    • 2
  • Kathleen A. McKeown
    • 1
    • 2
  1. 1.Departments of Biochemistry/Biophysics and PharmacyUniversity of CaliforniaSan FranciscoUSA
  2. 2.Molecular Biology Division, Veterans Administration Medical CenterSan FranciscoUSA

Personalised recommendations