Novel Therapeutic Target in PD: Experimental Models

  • Francesco Fornai
Part of the Advances in Behavioral Biology book series (ABBI, volume 57)


PC12 Cell Dopaminergic Neuron Lewy Body Proteasome Inhibition Nigrostriatal Pathway 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Betarbet R, Sherer TB, MacKanzie G, et al. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci 2000;3:1301–1306.PubMedCrossRefGoogle Scholar
  2. 2.
    Greenamyre JT, Hastings TG. Parkinson's-divergent causes, convergent mechanisms. Science 2004:304:1120–1122.PubMedCrossRefGoogle Scholar
  3. 3.
    Jenner P. The MPTP-treated primate as a model of motor complications in PD: primate model of motor complications. Neurology 2003:61:S4–S11.PubMedGoogle Scholar
  4. 4.
    Cohen G. Oxy-radical toxicity in catecholamine neurons. Neurotoxicology 1984;5:77–82.PubMedGoogle Scholar
  5. 5.
    Miller GW, Gainetdinov RR, Lavey AI, Caron MG. Dopamine transporter and neuronal injury. Trends Pharmacol Sci 1999;20:424–429.PubMedCrossRefGoogle Scholar
  6. 6.
    Sulzer D, Bogulavsky J, Larsen KE, et al. Neuromelanin biosynthesis is driven by excess cytosolic catecholamines not accumulated by synaptic vesicles. Proc Natl Acad Sci U S A 2000;97:11869–11874.PubMedCrossRefGoogle Scholar
  7. 7.
    Fornai F, Lenzi P, Gesi M, et al. Fine structure and biochemical mechanisms underlying nigrostriatal inclusions and cell death after proteasome inhibition. J Neurosci 2003;23:8955–8966.PubMedGoogle Scholar
  8. 8.
    Fornai F, Lenzi P, Gesi M, et al. Methamphetamine produces neuronal inclusions in the nigrostriatal system and in PC12 cells. J Neurochem 2004;88:114–123.PubMedCrossRefGoogle Scholar
  9. 9.
    Fornai F, Lenzi P, Frenzilli G, et al. DNA damage and ubiquitinated neuronal inclusions in the substantia nigra and striatum of mice following MDMA (ecstasy). Psychopharmacology 2004;173:353–363.PubMedCrossRefGoogle Scholar
  10. 10.
    Shimura H, Hattori N, Kubo S, et al. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet 2000;25:302–305.PubMedCrossRefGoogle Scholar
  11. 11.
    Liu Y, Fallon L, Lashuel HA, et al. The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease. Cell 2002;18:209–218.CrossRefGoogle Scholar
  12. 12.
    Spillantini MG, Schmidt ML, Lee VM, et al. Alpha-synuclein in Lewy bodies. Nature 1997;388:839–840.PubMedCrossRefGoogle Scholar
  13. 13.
    Conway KA, Rochet JC, Bieganski RM, Lansbury PT Jr. Kinetic stabilization of the alpha-synuclein protofibril by a dopamine alpha-synuclein adduct. Science 2001;294:1346–1349.PubMedCrossRefGoogle Scholar
  14. 14.
    Sulzer D. Alpha-synuclein and cytosolic dopamine: stabilizing a bad situation. Nat Med 2001;7:1280–1282.PubMedCrossRefGoogle Scholar
  15. 15.
    Fornai F, Lenzi P, Ferrucci M, et al. Occurrence of neuronal inclusions combined with increased nigral expression of α-synuclein within dopaminergic neurons following treatment with amphetamine derivatives in mice. Brain Res Bull 2005;65:405–413.PubMedCrossRefGoogle Scholar
  16. 16.
    Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 1997;276:2045–2047.PubMedCrossRefGoogle Scholar
  17. 17.
    Chung KK, Dawson VL, Dawson TM. The role of the ubiquitin-proteosomal pathway in Parkinson's disease and other neurodegenerative disorders. Trends Neurosci 2001;24:S7–S14.PubMedCrossRefGoogle Scholar
  18. 18.
    Feany MB, Bender WW. A Drosophila model of Parkinson's disease. Nature 2000;404:394–398.PubMedCrossRefGoogle Scholar
  19. 19.
    Masliah E, Rockenstein E, Veinbergs I, et al. Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implication for neurodegenerative disorders. Science 2000;287:1265–1269.PubMedCrossRefGoogle Scholar
  20. 20.
    Van der Putten H, Wiederhold KH, Probst A, et al. Neuropathology in mice expressing human alpha-synuclein. J Neurosci 2000;20:6021–6029.PubMedGoogle Scholar
  21. 21.
    Schapira AH, Olanow CW. Neuroprotection in Parkinson disease: mysteries, myths, and misconceptions. JAMA 2004;291:358–364.PubMedCrossRefGoogle Scholar
  22. 22.
    Fornai F, Schluter OM, Lenzi P, et al. tParkinson-like syndrome induced by continuous MPTP infusion: convergent roles of the ubiquitin-proteasome system and alpha-synuclein. Proc Natl Acad Sci U S A 2005;102:3413–3418.PubMedCrossRefGoogle Scholar
  23. 23.
    Luthman J, Fredriksson A, Sundstrom E, et al. Selective lesion of central dopamine or noradrenaline neuron systems in the neonatal rat: motor behavior and monoamine alterations at adult stage. Behav Brain Res 1989;33:267–277.PubMedCrossRefGoogle Scholar
  24. 24.
    Przedborski S, Levivier M, Jiang H, et al. Dose-dependent lesions of the dopaminergic nigrostriatal pathway induced by intrastriatal injection of 6-hydroxydopamine. Neuroscience 1995;67:631–647.PubMedCrossRefGoogle Scholar
  25. 25.
    Cohen G, Werner P. Free radicals, oxidative stress, and neurodegeneration. In: Calne DB (ed) Neurodegenerative Diseases. Saunders, Philadelphia, 1994, pp 139–161.Google Scholar
  26. 26.
    Hefti F, Melamed E, Wurtman RJ. Partial lesions of the dopaminergic nigrostriatal system in rat brain: biochemical characterization. Brain Res 1980;195:123–126.PubMedCrossRefGoogle Scholar
  27. 27.
    Bjorklund LM, Sanchez-Pernaute R, Chung S, et al. Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc Natl Acad Sci U S A 2002;99:2344–2349.PubMedCrossRefGoogle Scholar
  28. 28.
    Langston JW, Ballard P, Tetrud JW, Irwin I. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 1983;219:979–980.PubMedCrossRefGoogle Scholar
  29. 29.
    Przedborski S, Jackson-Lewis V, Vila M, et al. Free Radicals and nitric oxide toxicity in Parkinson′s disease. In: Gordin A, Kaakkola S, TerñÊinen H (eds). Parkinson's Disease. Lippincott, Philadelphia, 2003, pp 83–94.Google Scholar
  30. 30.
    Markey SP, Johannessen JN, Chiueh CC, et al. Intraneuronal generation of a pyridinium metabolite may cause drug-induced parkinsonism. Nature 1984;311:464–467.PubMedCrossRefGoogle Scholar
  31. 31.
    Mayer RA, Kindt MV, Heikkila RE. Prevention of the nigrostriatal toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by inhibitors of 3,4-dihydroxyphenylethylamine transport. J Neurochem 1986;47:1073–1079.PubMedCrossRefGoogle Scholar
  32. 32.
    D'Amato RJ, Lipman ZP, Snyder SH. Selectivity of the parkinsonian neurotoxin MPTP: toxic metabolite MPP+ binds to neuromelanin. Science 1986;231:987–989.PubMedCrossRefGoogle Scholar
  33. 33.
    Forno LS, Langston JW, DeLanney LE, et al. Locus ceruleus lesions and eosinophilic inclusions in MPTP-treated monkeys. Ann Neurol 1986;20:449–455.PubMedCrossRefGoogle Scholar
  34. 34.
    Forno LS, DeLanney LE, Irwin I, Langston JW. Similarities and differences between MPTP-induced parkinsonism and Parkinson's disease: neuropathologic considerations. Adv Neurol 1993;60:600–608.PubMedGoogle Scholar
  35. 35.
    Tatton NA, Kish SJ. 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 1997;77:1037–1048.PubMedCrossRefGoogle Scholar
  36. 36.
    Nicotra A, Parvez S. Apoptotic molecules and MPTP-induced cell death. Neurotoxicol Teratol 2002;24:599–605.PubMedCrossRefGoogle Scholar
  37. 37.
    Lee CS, Song EH, Park SY, Han ES. Combined effect of dopamine and MPP+ on membrane permeability in mitochondria and cell viability in PC12 cells. Neurochem Int 2003;43:147–154.PubMedCrossRefGoogle Scholar
  38. 38.
    Hoglinger GU, Feger F, Prigent A, et al. Chronic systemic complex I inhibition induces a hypokinetic multisystem degeneration in rats. J Neurochem 2003;84:491–503.PubMedCrossRefGoogle Scholar
  39. 39.
    Greenamyre JT, Betarbet R, Sherer TB. The rotenone model of Parkinson's disease: genes, environment and mitochondria. Parkinsonism Relat Disord 2003;9:S59-S64.PubMedCrossRefGoogle Scholar
  40. 40.
    Sherer TB, Betarbet R, Testa CM, et al. Mechanism of toxicity in rotenone models of Parkinson's disease. J Neurosci 2003;23:10756–10764.PubMedGoogle Scholar
  41. 41.
    Marking L. Oral toxicity of rotenone to mammals. US Fish Wildlife Serv Invest Fish Control 1988;4:1.Google Scholar
  42. 42.
    Ferrante RJ, Schulz JB, Kowall NW, Beal MF. Systemic administration of rotenone produces selective damage in the striatum and globus pallidus, but not in the substantia nigra. Brain Res 1997l;753:157–162.CrossRefGoogle Scholar
  43. 43.
    Heikkila RE, Nicklas WJ, Vyas I, Duvoisin RC. Dopaminergic toxicity of rotenone and the 1-methyl-4-phenylpyridinium ion after their stereotaxic administration to rats: implication for the mechanism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity. Neurosci Lett 1985;62:389–394.PubMedCrossRefGoogle Scholar
  44. 44.
    Thiffault C, Langston JW, Di Monte DA. Increased striatal dopamine turnover following acute administration of rotenone to mice. Brain Res 2000;885:283–288.PubMedCrossRefGoogle Scholar
  45. 45.
    Hensley K, Pye QN, Maidt ML, et al. Interaction of alpha-phenyl-N-tert-butyl nitrone and alternative electron acceptors with complex I indicates a substrate reduction site upstream from the rotenone binding site. J Neurochem 1998;71:2549–2557.PubMedCrossRefGoogle Scholar
  46. 46.
    Testa CM, Sherer TB, Greenamyre JT. Rotenone induces oxidative stress and dopaminergic neuron damage in organotypic substantia nigra cultures. Mol Brain Res 2005;134:109–118.PubMedCrossRefGoogle Scholar
  47. 47.
    Lee HJ, Shin SY, Choi C, et al. Formation and removal of alpha-synuclein aggregates in cells exposed to mitochondrial inhibitors. J Biol Chem 2002;277:5411–5417.PubMedCrossRefGoogle Scholar
  48. 48.
    Sherer TB, Betarbet R, Stout AK, et al. An in vitro model of Parkinson's disease: linking mitochondrial impairment to altered alpha-synuclein metabolism and oxidative damage. J Neurosci 2002;22:7006–7015.PubMedGoogle Scholar
  49. 49.
    Sherer TB, Kim JH, Betarbet R, Greenamyre TJ. Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and α-synuclein aggregation. Exp Neurol 2003;179:9–16.PubMedCrossRefGoogle Scholar
  50. 50.
    Nicklas WJ, Vyas I, Heikkila RE. 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;36:2503–2508.PubMedCrossRefGoogle Scholar
  51. 51.
    Ramsay RR, Salach JI, Singer TP. Uptake of the neurotoxin 1-methyl-4-phenylpyridine (MPP+) by mitochondria and its relation to the inhibition of the mitochondrial oxidation of NAD+-linked substrates by MPP+. Biochem Biophys Res Commun 1986;134:743–748.PubMedCrossRefGoogle Scholar
  52. 52.
    Dauer W, Kholodilov N, Vila M, et al. Resistance of alpha-synuclen null mice to the parkinsonian neurotoxin MPTP. Proc Natl Acad Sci U S A 2002;99:14524–14529.PubMedCrossRefGoogle Scholar
  53. 53.
    Drolet RE, Behrouz B, Lookingland KJ, Goudreau JL. Mice lacking alpha-synuclein have an attenuated loss of striatal dopamine following prolonged chronic MPTP administration. Neurotoxicology 2004;25:761–769.PubMedCrossRefGoogle Scholar
  54. 54.
    Lansbury PT Jr, Brice A. Genetics of Parkinson's disease and biochemical studies of implicated gene products. Curr Opin Cell Biol 2002;14:653–660.PubMedCrossRefGoogle Scholar
  55. 55.
    Dauer W, Przedborski S. Parkinson's disease: mechanisms and models. Neuron 2003;39:889–909.PubMedCrossRefGoogle Scholar
  56. 56.
    Kruger R. Genes in familial parkinsonism and their role in sporadic Parkinson's disease. J Neurol 2004;S6:2–6.Google Scholar
  57. 57.
    Kitada T, Asakawa S, Hattori N, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 1998;392:605–608.PubMedCrossRefGoogle Scholar
  58. 58.
    Oliveira SA, Scott WK, Martin ER, et al. Parkin mutations and susceptibility alleles in late-onset Parkinson's disease. Ann Neurol 2003;53:624–629.PubMedCrossRefGoogle Scholar
  59. 59.
    Mizuno Y, Hattori N, Mori H, et al. Parkin and Parkinson's disease. Curr Opin Neurol 2001;14:477–482.PubMedCrossRefGoogle Scholar
  60. 60.
    Petrucelli L, O'Farrell C, Lockhart PJ, et al. Parkin protects against the toxicity associated with mutant alpha-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons. Neuron 2002;36:1007–1019.PubMedCrossRefGoogle Scholar
  61. 61.
    Perez FA, Palmiter RD. Parkin-deficent mice are not a robust model of parkinsonism. Proc Natl Acad Sci U S A 2005;102:2174–2179.PubMedCrossRefGoogle Scholar
  62. 62.
    Imai Y, Soda M, Takahashi R. Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin-protein ligase activity. J Biol Chem 2000;275:35661–35664.PubMedCrossRefGoogle Scholar
  63. 63.
    Lo Bianco C, Schneider BL, Bauer M, et al. Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an alpha-synuclein rat model of Parkinson's disease. Proc Natl Acad Sci U S A 2004;101:17510–17515.PubMedCrossRefGoogle Scholar
  64. 64.
    Leroy E, Boyer R, Auburger G, et al. The ubiquitin pathway in Parkinson's disease. Nature 1998;395:451–452.PubMedCrossRefGoogle Scholar
  65. 65.
    Bonifati V, Rizzu P, van Baren MJ, et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 2003;299:256–259.PubMedCrossRefGoogle Scholar
  66. 66.
    Mitsumoto A, Nakagawa Y. DJ-1 is an indicator for endogenous reactive oxygen species elicited by endotoxin. Free Radic Res 2001;35:885–893.PubMedCrossRefGoogle Scholar
  67. 67.
    Kim RH, Smith PD, Aleyasin H, et al. Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress. Proc Natl Acad Sci U S A 2005;102:5215–5120.PubMedCrossRefGoogle Scholar
  68. 68.
    Dev KK, Hofele K, Barbieri S, et al. Part II. α-Synuclein and its molecular pathophysiological role in neurodegenerative disease. Neuropharmacology 2003;45:14–44.PubMedCrossRefGoogle Scholar
  69. 69.
    Larsen EK, Sulzer D. Autophagy in neurons: a review. Histol Histopathol 2002;17:897–908.PubMedGoogle Scholar
  70. 70.
    Kruger R, Kuhn W, Mueller T, et al. Ala30Pro mutation in the gene encoding α-synuclein in Parkinson's disease. Nat Genet 1998;18:106–108.PubMedCrossRefGoogle Scholar
  71. 71.
    Zarranz JJ, Alegre J, Gomez-Esteban JC, et al. The new mutation, E46K, of α-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 2004;55:164–173.PubMedCrossRefGoogle Scholar
  72. 72.
    Recchia A, Debetto P, Negro A, et al. α-Synuclein and Parkinson's disease. FASEB J 2004;18:617–626.PubMedCrossRefGoogle Scholar
  73. 73.
    Sidhu A, Wersinger C, Vernier P. Does α-synuclein modulate dopaminergic synaptic content and tone at the synapse? FASEB J 2004;18:637–647.PubMedCrossRefGoogle Scholar
  74. 74.
    Lotharius J, Brundin P. Impaired dopamine storage resulting from alpha-synuclein mutations may contribute to the pathogenesis of Parkinson's disease. Hum Mol Gen 2002;11;2395–2407.PubMedCrossRefGoogle Scholar
  75. 75.
    Singleton AB, Farrer M, Jhonson J, et al. Alpha-synuclein locus triplication causes Parkinson's disease. Science 2003;302:841.PubMedCrossRefGoogle Scholar
  76. 76.
    Farrer M, Kachergus J, Forno L, et al. Comparison of kindreds with parkinsonism and alpha-synuclein genomic multiplications. Ann Neurol 2004;55:174–179.PubMedCrossRefGoogle Scholar
  77. 77.
    Kirik D, Rosenblad C, Burger C, et al. Parkinson-like neurodegeneration induced by targeted overexpression of alpha-synuclein in the nigrostriatal system. J Neurosci 2002;22:2780–2791.PubMedGoogle Scholar
  78. 78.
    Kleven MS, Seiden LS. Repeated injection of cocaine potentiates methamphetamine-induced toxicity to dopamine-containing neurons in rat striatum. Brain Res 1991;557:340–343.PubMedCrossRefGoogle Scholar
  79. 79.
    Stefanis L, Larsen KE, Rideout J, et al. Expression of A53T mutant but not wild-type α- synuclein in PC12 cells induces alterations of the ubiquitin-dependent degradation system, loss of dopamine release, and autophagic cell death. J Neurosci 2001;21: 9549–9560.PubMedGoogle Scholar
  80. 80.
    Ciechanover A, Orian A, Schwartz AL. Ubiquitin-mediated proteolysis: biological regulation via destruction. Bioessay 2000;22:442–451.CrossRefGoogle Scholar
  81. 81.
    McNaught KS, Belizaire R, Isacson O, et al. Altered proteasomal function in sporadic Parkinson's disease. Exp Neurol 2003;179:38–46.PubMedCrossRefGoogle Scholar
  82. 82.
    McNaught KS, Belizaire R, Jenner P, et al. Selective loss of 20S proteasome alpha-subunits in the substantia nigra pars compacta in Parkinson's disease. Neurosci Lett 2002;326:155–158.PubMedCrossRefGoogle Scholar
  83. 83.
    McNaught KS, Bjorklund LM, Belizaire R, et al. Proteasome inhibition causes nigral degeneration with inclusion bodies in rats. Neuroreport 2002;13:1437–1441.PubMedCrossRefGoogle Scholar
  84. 84.
    Betarbet R, Sherer TB, Greenamyre JT. Ubiquitin-proteasome system and Parkinson's diseases. Exp Neurol 2005;191:S17–S27.PubMedCrossRefGoogle Scholar
  85. 85.
    Forno LS. Neuropathology of Parkinson's disease. J Neuropathol Exp Neurol 1996;55:259–272.PubMedCrossRefGoogle Scholar
  86. 86.
    Sullivan PG, Dragicevic NB, Deng JH, et al. Proteasome inhibition alters neuronal mitochondrial homeostasis and mitochondria turnover. J Biol Chem 2004;279:20699–20707.PubMedCrossRefGoogle Scholar
  87. 87.
    Fornai F, Lenzi P, Gesi M, et al. Recent knowledge on molecular components of Lewy bodies discloses future therapeutic strategies in Parkinson's disease. Curr Drug Targets CNS Neurol Disord 2003;2:149–152.PubMedCrossRefGoogle Scholar
  88. 88.
    Hartl FU, Hayer-Hartl M. Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 2002;295:1852–1858.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Francesco Fornai
    • 1
  1. 1.Department of Human Morphology and Applied BiologyUniversity of Pisa56126 PisaItaly

Personalised recommendations