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Protocol for the MPTP mouse model of Parkinson's disease


This protocol describes our method of producing a reliable mouse model of Parkinson's disease (PD) using the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We discuss the particulars of the model, provide key references and outline what investigators need to know to develop the MPTP mouse model of PD safely and successfully. Completion of this protocol depends on the regimen of MPTP used and on the actual planned studies, which often range from 7 to 30 d. This protocol calls for implementation of safety measures and for the acquisition of several pieces of equipment, which are a one-time investment worth making if one elects to use this model on a regular basis.

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Figure 1: Mouse brain levels of dopamine (DA) and its main metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA).
Figure 2: Immunostaining of tyrosine hydroxylase (TH)–positive neurons in the substantia nigra pars compacta (SNpc) and terminals in the striatum.
Figure 3: MPTP and MPP+ quantification in blood and brain tissues.


  1. Fahn, S., Przedborski, S. Parkinsonism, In Merritt's Neurology (ed. Rowland, L.P.) 828–846 (Lippincott Williams & Wilkins, New York, 2005).

    Google Scholar 

  2. Dauer, W. & Przedborski, S. Parkinson's disease: mechanisms and models. Neuron 39, 889–909 (2003).

    CAS  Article  Google Scholar 

  3. Przedborski, S. & Tieu, K. Toxic animal models. In Neurodegenerative diseases: Neurobiology, pathogenesis and therapeutics (eds. Beal, M.F., Lang, A.E. & Ludolph, A.) 196–221 (Cambridge, New York, 2005).

    Chapter  Google Scholar 

  4. Langston, J.W., Ballard, P. & Irwin, I. Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219, 979–980 (1983).

    CAS  Article  Google Scholar 

  5. Sotelo, C., Javoy, F., Agid, Y. & Glowinski, J. Injection of 6-hydroxydopamine in the substantia nigra of the rat. I. Morphological study. Brain Res. 58, 269–290 (1973).

    CAS  Article  Google Scholar 

  6. Betarbet, R. et al. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat. Neurosci. 3, 1301–1306 (2000).

    CAS  Article  Google Scholar 

  7. Bove, J. et al. Proteasome inhibition and Parkinson's disease modeling. Ann. Neurol. 60, 260–264 (2006).

    CAS  Article  Google Scholar 

  8. Przedborski, S. et al. The parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): a technical review of its utility and safety. J. Neurochem. 76, 1265–1274 (2001).

    CAS  Article  Google Scholar 

  9. Sonsalla, P.K. & Heikkila, R.E. The influence of dose and dosing interval on MPTP-induced dopaminergic neurotoxicity in mice. Eur. J. Pharmacol. 129, 339–345 (1986).

    CAS  Article  Google Scholar 

  10. Fornai, F. et al. Parkinson-like syndrome induced by continuous MPTP infusion: Convergent roles of the ubiquitin-proteasome system and \{alpha}-synuclein. Proc. Natl. Acad. Sci. USA 102, 3413–3418 (2005).

    CAS  Article  Google Scholar 

  11. Meredith, G.E. et al. Lysosomal malfunction accompanies alpha-synuclein aggregation in a progressive mouse model of Parkinson's disease. Brain Res. 956, 156–165 (2002).

    CAS  Article  Google Scholar 

  12. Heikkila, R.E., Sieber, B.A., Manzino, L. & Sonsalla, P.K. Some features of the nigrostriatal dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the mouse. Mol. Chemic. Neuropathol. 10, 171–183 (1989).

    CAS  Article  Google Scholar 

  13. Giovanni, A., Sieber, B.A., Heikkila, R.E. & Sonsalla, P.K. Correlation between the neostriatal content of the 1-methyl-4-phenylpyridinium species and dopaminergic neurotoxicity following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration to several strains of mice. J. Pharmacol. Exp. Ther. 257, 691–697 (1991).

    CAS  PubMed  Google Scholar 

  14. Giovanni, A., Sieber, B.-A., Heikkila, R.E. & Sonsalla, P.K. Studies on species sensitivity to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Part 1: Systemic administration. J. Pharmacol. Exp. Ther. 270, 1000–1007 (1994).

    CAS  PubMed  Google Scholar 

  15. Giovanni, A., Sonsalla, P.K. & Heikkila, R.E. Studies on species sensitivity to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Part 2: Central administration of 1-methyl-4-phenylpyridinium. J. Pharmacol. Exp. Ther. 270, 1008–1014 (1994).

    CAS  PubMed  Google Scholar 

  16. Miller, D.B., Ali, S.F., O'Callaghan, J.P. & Laws, S.C. The impact of gender and estrogen on striatal dopaminergic neurotoxicity. Ann. N. Y. Acad. Sci. 844, 153–165 (1998).

    CAS  Article  Google Scholar 

  17. Staal, R.G. & Sonsalla, P.K. Inhibition of brain vesicular monoamine transporter (VMAT2) enhances 1-methyl-4-phenylpyridinium neurotoxicity in vivo in rat striata. J. Pharmacol. Exp. Ther. 293, 336–342 (2000).

    CAS  PubMed  Google Scholar 

  18. Javitch, J.A., D'Amato, R.J., Strittmatter, S.M. & Snyder, S.H. Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: uptake of the metabolite N-methyl-4-phenylpyridinium by dopamine neurons explain selective toxicity. Proc. Natl. Acad. Sci. USA 82, 2173–2177 (1985).

    CAS  Article  Google Scholar 

  19. Liu, Y., Roghani, A. & Edwards, R.H. Gene transfer of a reserpine-sensitive mechanism of resistance to N-methyl-4-phenylpyridinium. Proc. Natl. Acad. Sci. USA 89, 9074–9078 (1992).

    CAS  Article  Google Scholar 

  20. Ramsay, R.R. & Singer, T.P. 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. 261, 7585–7587 (1986).

    CAS  PubMed  Google Scholar 

  21. Jackson-Lewis, V., Jakowec, M., Burke, R.E. & Przedborski, S. Time course and morphology of dopaminergic neuronal death caused by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Neurodegeneration 4, 257–269 (1995).

    CAS  Article  Google Scholar 

  22. Tatton, N.A. & Kish, S.J. In situ detection of apoptotic nuclei in the substantia nigra compacta of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice using terminal deoxynucleotidyl transferase labelling and acridine orange staining. Neuroscience. 77, 1037–1048 (1997).

    CAS  Article  Google Scholar 

  23. Liberatore, G. et al. Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Nat. Med. 5, 1403–1409 (1999).

    CAS  Article  Google Scholar 

  24. Przedborski, S. et al. Transgenic mice with increased Cu/Zn-superoxide dismutase activity are resistant to N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity. J. Neurosci. 12, 1658–1667 (1992).

    CAS  Article  Google Scholar 

  25. Youdim, M.B.H. Assay and purification of brain monoamine oxidase, in Eds. Marks, N. & Rodnight, R. Research Methods in Neurochemistry, Vol. 3, 167–208 (Plenum Press, New York, 1975).

    Chapter  Google Scholar 

  26. Tieu, K. et al. D-beta-hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease. J. Clin. Invest. 112, 892–901 (2003).

    CAS  Article  Google Scholar 

  27. Chiba, K., Kubota, E., Miyakawa, T., Kato, Y. & Ishizaki, T. Characterization of hepatic microsomal metabolism as an in vivo detoxication pathway of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice. J. Pharmacol. Exp. Ther. 246, 1108–1115 (1988).

    CAS  PubMed  Google Scholar 

  28. Yang, S.C., Markey, S.P., Bankiewicz, K.S., London, W.T. & Lunn, G. Recommended safe practices for using the neurotoxin MPTP in animal experiments. Lab. Anim. Sci. 38, 563–567 (1988).

    CAS  PubMed  Google Scholar 

  29. Johannessen, J.N., Chiueh, C.C., Herkenham, M. & Markey, C.J. Relationship of the in vivo metabolism of MPTP to toxicity. In MPTP: A Neurotoxin Producing a Parkinsonian Syndrome (eds. Markey, S.P., Castagnoli, N. Jr., Trevor, A.J. & Kopin, I.J.) 173–189 (Academic Press, Orlando, 1986).

    Google Scholar 

  30. Markey, S.P., Johannessen, J.N., Chiueh, C.C., Burns, R.S. & Herkenham, M.A. Intraneuronal generation of a pyridinium metabolite may cause drug-induced parkinsonism. Nature 311, 464–467 (1984).

    CAS  Article  Google Scholar 

  31. Kiernan, J.A. Histological and Histochemical Methods Theory and Practice (Butterworth Heinemann, Oxford, 1999).

    Google Scholar 

  32. Vila, M. et al. 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. USA 98, 2837–2842 (2001).

    CAS  Article  Google Scholar 

  33. Shinka, T., Castagnoli, N., Jr., Wu, E.Y., Hoag, M.K. & Trevor, A.J. Cation-exchange high-performance liquid chromatography assay for the nigrostriatal toxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and its monoamine oxidase B generated metabolites in brain tissues. J. Chromatogr. 398, 279–287 (1987).

    CAS  Article  Google Scholar 

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The authors wish to thank Drs. Cristina Malagelada Grau, Delphine Prou, Du-Chu Wu, Diane Re and Chun Zhou for their insightful comments on this manuscript. The authors wish to acknowledge the support of the National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke Grants R01 NS42269, P50 NS38370 and P01 NS11766; NIH/National Institute of Aging Grant AG R01 21617; National Institute of Environmental Health Sciences Grant ES013177; US Department of Defense Grant DAMD 17-03-1; the Parkinson's Disease Foundation Grant CU51523606, and the Muscular Dystrophy Association/Wings-over-Wall Street.

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Correspondence to Serge Przedborski.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Data

MPTP Core Experiment Log (PDF 15 kb)

Supplementary Information

MPTP Core Experiment Log (PDF 19 kb)

Supplementary Video

Mouse brain dissection tutorial (MOV 61856 kb)

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Jackson-Lewis, V., Przedborski, S. Protocol for the MPTP mouse model of Parkinson's disease. Nat Protoc 2, 141–151 (2007).

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