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PMID: 15377875 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S. Review

MPTP as a mitochondrial neurotoxic model of Parkinson's disease.

Journal of bioenergetics and biomembranes ·Vol. 36 ·No. 4 ·2004-08-00 ·Pages 375-9

Przedborski S, Tieu K, Perier C, Vila M

Abstract

1-Methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a potent neurotoxin extensively used to model Parkinson's disease (PD). A cascade of deleterous events, in which mitochondria play a pivotal role, drives MPTP neurotoxicity. How mitochondria are affected by MPTP and how their defect contributes to the demise of dopaminergic neurons in this model of PD are discussed in this review.

MeSH Terms
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/administration & dosage Adenosine Triphosphate/metabolism Animals Apoptosis/drug effects Disease Models, Animal MPTP Poisoning/chemically induced,metabolism Mice Mitochondria/drug effects,metabolism Mitochondrial Diseases/chemically induced,metabolism Mitochondrial Proteins/metabolism Neurons/drug effects,metabolism Neurotoxins/toxicity Rats Reactive Oxygen Species/metabolism
Chemicals
Mitochondrial Proteins Neurotoxins Reactive Oxygen Species Adenosine Triphosphate 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Przedborski Serge
Department of Neurology, Columbia University, New York, New York 10032, USA. sp30@columbia.edu
Tieu Kim
Perier Celine
Vila Miquel
References (46)
46 references, click to expand
  1. Rapid ATP loss caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mouse brain.
    J Neurochem. 1991 Jul;57(1):348-51 PMID: 2051170
  2. Uptake and accumulation of 1-methyl-4-phenylpyridinium by rat liver mitochondria measured using an ion-selective electrode.
    Biochem J. 1992 Dec 1;288 ( Pt 2):439-43 PMID: 1463448
  3. Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 1-methyl-4-phenylpyridinium ion on ATP levels of mouse brain synaptosomes.
    J Neurochem. 1990 Apr;54(4):1295-301 PMID: 2313288
  4. Biochemical events in the development of parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
    J Neurochem. 1987 Jul;49(1):1-8 PMID: 3495634
  5. D-beta-hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease.
    J Clin Invest. 2003 Sep;112(6):892-901 PMID: 12975474
  6. 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 Biochem Biophys. 1987 Dec;259(2):645-9 PMID: 2827583
  7. Specificity of pyridinium inhibitors of the ubiquinone reduction sites in mitochondrial complex I.
    J Biol Chem. 1998 Jul 10;273(28):17368-74 PMID: 9651320
  8. Some features of the nigrostriatal dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the mouse.
    Mol Chem Neuropathol. 1989 Jun;10(3):171-83 PMID: 2669769
  9. Studies on the molecular mechanism of bioactivation of the selective nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
    Drug Metab Dispos. 1985 May-Jun;13(3):342-7 PMID: 2861994
  10. Energy-dependent uptake of N-methyl-4-phenylpyridinium, the neurotoxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, by mitochondria.
    J Biol Chem. 1986 Jun 15;261(17):7585-7 PMID: 3486869
  11. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridine (MPP+) cause rapid ATP depletion in isolated hepatocytes.
    Biochem Biophys Res Commun. 1986 May 29;137(1):310-5 PMID: 3487319
  12. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model: a tool to explore the pathogenesis of Parkinson's disease.
    Ann N Y Acad Sci. 2003 Jun;991:189-98 PMID: 12846987
  13. Studies on the 1-methyl-4-phenyl-2,3-dihydropyridinium species 2,3-MPDP+, the monoamine oxidase catalyzed oxidation product of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
    J Med Chem. 1985 Oct;28(10):1432-6 PMID: 3876442
  14. Energy-driven uptake of N-methyl-4-phenylpyridine by brain mitochondria mediates the neurotoxicity of MPTP.
    Life Sci. 1986 Aug 18;39(7):581-8 PMID: 3488484
  15. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and free radicals in vitro.
    Biochem Pharmacol. 1988 Dec 1;37(23):4573-4 PMID: 2849450
  16. Characterization of the inhibitory mechanism of 1-methyl-4-phenylpyridinium and 4-phenylpyridine analogs in inner membrane preparations.
    J Biol Chem. 1994 Feb 4;269(5):3167-74 PMID: 8106350
  17. Relation of superoxide generation and lipid peroxidation to the inhibition of NADH-Q oxidoreductase by rotenone, piericidin A, and MPP+.
    Biochem Biophys Res Commun. 1992 Nov 30;189(1):47-52 PMID: 1333196
  18. Membrane potential and surface potential in mitochondria: uptake and binding of lipophilic cations.
    J Membr Biol. 1984;81(2):127-38 PMID: 6492133
  19. Enhancement by tetraphenylboron of inhibition of mitochondrial respiration induced by 1-methyl-4-phenylpyridinium ion (MPP(+)).
    Neurochem Int. 1988;12(4):525-31 PMID: 20501261
  20. Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 1-methyl-4-phenylpyridinium ion on activities of the enzymes in the electron transport system in mouse brain.
    J Neurochem. 1987 Jun;48(6):1787-93 PMID: 3106573
  21. Entry of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine into the rat brain.
    J Pharmacol Exp Ther. 1989 Jun;249(3):744-8 PMID: 2786562
  22. MPTP: current concepts and controversies.
    Clin Neuropharmacol. 1986;9(6):485-507 PMID: 3542203
  23. Interaction of 1-methyl-4-phenylpyridinium ion (MPP+) and its analogs with the rotenone/piericidin binding site of NADH dehydrogenase.
    J Neurochem. 1991 Apr;56(4):1184-90 PMID: 2002336
  24. NADH-quinone oxidoreductase: PSST subunit couples electron transfer from iron-sulfur cluster N2 to quinone.
    Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):4149-53 PMID: 10097178
  25. Time course and morphology of dopaminergic neuronal death caused by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
    Neurodegeneration. 1995 Sep;4(3):257-69 PMID: 8581558
  26. Threshold effects and control of oxidative phosphorylation in nonsynaptic rat brain mitochondria.
    J Neurochem. 1996 Apr;66(4):1617-24 PMID: 8627318
  27. Absence of MPTP-induced neuronal death in mice lacking the dopamine transporter.
    Exp Neurol. 1999 Feb;155(2):268-73 PMID: 10072302
  28. Studies on the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: inhibition of NAD-linked substrate oxidation by its metabolite, 1-methyl-4-phenylpyridinium.
    J Neurochem. 1986 May;46(5):1501-7 PMID: 3485701
  29. Inhibition of mitochondrial alpha-ketoglutarate dehydrogenase by 1-methyl-4-phenylpyridinium ion.
    Biochem Biophys Res Commun. 1987 Mar 30;143(3):971-6 PMID: 3494449
  30. Protection against the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine by monoamine oxidase inhibitors.
    Nature. 1984 Oct 4-10;311(5985):467-9 PMID: 6332989
  31. Evidence that the inhibition sites of the neurotoxic amine 1-methyl-4-phenylpyridinium (MPP+) and of the respiratory chain inhibitor piericidin A are the same.
    Biochem J. 1991 Jan 15;273(Pt 2):481-4 PMID: 1991043
  32. Distribution of type B monoamine oxidase immunoreactivity in the cat brain with reference to enzyme histochemistry.
    Neuroscience. 1991;44(1):185-204 PMID: 1770996
  33. 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 U S A. 1985 Apr;82(7):2173-7 PMID: 3872460
  34. Reactivation of NADH dehydrogenase (complex I) inhibited by 1-methyl-4-(4'-alkylphenyl)pyridinium analogues: a clue to the nature of the inhibition site.
    J Neurochem. 1993 Oct;61(4):1546-8 PMID: 8377005
  35. Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine.
    Life Sci. 1985 Jul 1;36(26):2503-8 PMID: 2861548
  36. Bax ablation prevents dopaminergic neurodegeneration in the 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease.
    Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2837-42 PMID: 11226327
  37. Functional coupling of PSST and ND1 subunits in NADH:ubiquinone oxidoreductase established by photoaffinity labeling.
    Biochim Biophys Acta. 2001 Jul 2;1506(1):79-87 PMID: 11418099
  38. Intraneuronal generation of a pyridinium metabolite may cause drug-induced parkinsonism.
    Nature. 1984 Oct 4-10;311(5985):464-7 PMID: 6332988
  39. Manganese superoxide dismutase overexpression attenuates MPTP toxicity.
    Neurobiol Dis. 1998 Oct;5(4):253-8 PMID: 9848095
  40. Inhibition of mitochondrial respiration by analogs of 4-phenylpyridine and 1-methyl-4-phenylpyridinium cation (MPP+), the neurotoxic metabolite of MPTP.
    Biochem Biophys Res Commun. 1987 Oct 29;148(2):684-93 PMID: 3500717
  41. 1-Methyl-4-phenylpyridinium (MPP+) induces NADH-dependent superoxide formation and enhances NADH-dependent lipid peroxidation in bovine heart submitochondrial particles.
    Biochem Biophys Res Commun. 1990 Aug 16;170(3):1049-55 PMID: 2167668
  42. Mice with a partial deficiency of manganese superoxide dismutase show increased vulnerability to the mitochondrial toxins malonate, 3-nitropropionic acid, and MPTP.
    Exp Neurol. 2001 Jan;167(1):189-95 PMID: 11161607
  43. Piperidine derivatives; 4-arylpiperidines.
    J Org Chem. 1947 Nov;12(6):894-903 PMID: 18919742
  44. Structural dependence of the inhibition of mitochondrial respiration and of NADH oxidase by 1-methyl-4-phenylpyridinium (MPP+) analogs and their energized accumulation by mitochondria.
    Proc Natl Acad Sci U S A. 1989 Dec;86(23):9168-72 PMID: 2594758
  45. Parkinson's disease: mechanisms and models.
    Neuron. 2003 Sep 11;39(6):889-909 PMID: 12971891
  46. Probing the ubiquinone reduction site of mitochondrial complex I using novel cationic inhibitors.
    J Biol Chem. 1997 Jun 27;272(26):16176-83 PMID: 9195916
Article Info
Journal
Journal of bioenergetics and biomembranes
Abbr.
J Bioenerg Biomembr
ISSN
0145-479X
DOI
10.1023/B:JOBB.0000041771.66775.d5
Email
sp30@columbia.edu
Published
2004-08-00
Pages
375-9
Language
English
Region
United States
NLM ID
7701859
Subset
IM
Grants
NINDS NIH HHS · NS42269 · United States
NINDS NIH HHS · P01 NS11766-27A1 · United States
NINDS NIH HHS · P50 NS38370 · United States
NIA NIH HHS · R01 AG021617-01 · United States
NINDS NIH HHS · R01 NS38586 · United States
NINDS NIH HHS · R29 NS37345 · United States
External Links
PubMed source DOI: 10.1023/B:JOBB.0000041771.66775.d5 View journal details
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