Experimental Brain Research

, Volume 173, Issue 2, pp 196–204

Parkinson’s disease: a rethink of rodent models

  • Heather L. Melrose
  • Sarah J. Lincoln
  • Glenn M. Tyndall
  • Matthew J. Farrer
Review

Abstract

Parkinson’s disease (PD) is a multifactorial disease with a complex etiology that results from genetic risk factors, environmental exposures and most likely a combination of both. Rodent models of parkinsonism aim to reproduce key pathogenic features of the syndrome including movement disorder induced by the progressive loss of dopaminergic neurons in the substantia nigra, accompanied by the formation of α-synuclein containing Lewy body inclusions. Despite the creation of many excellent models, both chemically induced and genetically engineered, there is none that accurately demonstrates these features. Recent pathological staging studies in man have also emphasized the significant non-CNS component of PD that has yet to be tackled. Herein, we summarize rodent models of PD and what they offer to the field, and suggest future challenges and opportunities.

Keywords

Parkinson’s disease Mouse Toxin Genetic 

References

  1. Abeliovich A, Schmitz Y, Farinas I, Choi-Lundberg D, Ho WH, Castillo PE, Shinsky N, Verdugo JM, Armanini M, Ryan A, Hynes M, Phillips H, Sulzer D, Rosenthal A (2000) Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25:239–252PubMedCrossRefGoogle Scholar
  2. Andorfer C, Kress Y, Espinoza M, de Silva R, Tucker KL, Barde YA, Duff K, Davies P (2003) Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J Neurochem 86:582–590PubMedCrossRefGoogle Scholar
  3. Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT (2000) Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 3:1301–1306PubMedCrossRefGoogle Scholar
  4. Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M, van Dongen JW, Vanacore N, van Swieten JC, Brice A, Meco G, van Duijn CM, Oostra BA, Heutink P (2003) Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299:256–259PubMedCrossRefGoogle Scholar
  5. Bove J, Prou D, Perier C, Przedborski S (2005) Toxin-induced models of Parkinson’s disease. NeuroRx 2:484–494PubMedCrossRefGoogle Scholar
  6. Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K (2004) Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 318:121–134PubMedCrossRefGoogle Scholar
  7. Cabin DE, Shimazu K, Murphy D, Cole NB, Gottschalk W, McIlwain KL, Orrison B, Chen A, Ellis CE, Paylor R, Lu B, Nussbaum RL (2002) Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking alpha-synuclein. J Neurosci 22:8797–8807PubMedGoogle Scholar
  8. Cabin DE, Gispert-Sanchez S, Murphy D, Auburger G, Myers RR, Nussbaum RL (2005) Exacerbated synucleinopathy in mice expressing A53T SNCA on a SNCA null background. Neurobiol Aging 26:25–35PubMedCrossRefGoogle Scholar
  9. Chandra S, Fornai F, Kwon HB, Yazdani U, Atasoy D, Liu X, Hammer RE, Battaglia G, German DC, Castillo PE, Sudhof TC (2004) Double-knockout mice for alpha- and beta-synucleins: effect on synaptic functions. Proc Natl Acad Sci USA 101:14966–14971PubMedCrossRefGoogle Scholar
  10. Chen L, Feany MB (2005) Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease. Nat Neurosci 8:657–663PubMedCrossRefGoogle Scholar
  11. Chen L, Cagniard B, Mathews T, Jones S, Koh HC, Ding Y, Carvey PM, Ling Z, Kang UJ, Zhuang X (2005) Age-dependent motor deficits and dopaminergic dysfunction in DJ-1 null mice. J Biol Chem 280:21418–21426PubMedCrossRefGoogle Scholar
  12. Cory-Slechta DA, Thiruchelvam M, Barlow BK, Richfield EK (2005) Developmental pesticide models of the Parkinson disease phenotype. Environ Health Perspect 113:1263–1270PubMedCrossRefGoogle Scholar
  13. Dauer W, Kholodilov N, Vila M, Trillat AC, Goodchild R, Larsen KE, Staal R, Tieu K, Schmitz Y, Yuan CA, Rocha M, Jackson-Lewis V, Hersch S, Sulzer D, Przedborski S, Burke R, Hen R (2002) Resistance of alpha-synuclein null mice to the parkinsonian neurotoxin MPTP. Proc Natl Acad Sci USA 99:14524–14529PubMedCrossRefGoogle Scholar
  14. Drolet RE, Behrouz B, Lookingland KJ, Goudreau JL (2004) Mice lacking alpha-synuclein have an attenuated loss of striatal dopamine following prolonged chronic MPTP administration. Neurotoxicology 25:761–769PubMedCrossRefGoogle Scholar
  15. Duff K, Knight H, Refolo LM, Sanders S, Yu X, Picciano M, Malester B, Hutton M, Adamson J, Goedert M, Burki K, Davies P (2000) Characterization of pathology in transgenic mice over-expressing human genomic and cDNA tau transgenes. Neurobiol Dis 7:87–98PubMedCrossRefGoogle Scholar
  16. Fahn S (2003) Description of Parkinson’s disease as a clinical syndrome. Ann NY Acad Sci 991:1–14PubMedCrossRefGoogle Scholar
  17. Fernagut PO, Chesselet MF (2004) Alpha-synuclein and transgenic mouse models. Neurobiol Dis 17:123–130PubMedCrossRefGoogle Scholar
  18. Fleming SM, Salcedo J, Fernagut PO, Rockenstein E, Masliah E, Levine MS, Chesselet MF (2004) Early and progressive sensorimotor anomalies in mice overexpressing wild-type human alpha-synuclein. J Neurosci 24:9434–9440PubMedCrossRefGoogle Scholar
  19. Frasier M, Walzer M, McCarthy L, Magnuson D, Lee JM, Haas C, Kahle P, Wolozin B (2005) Tau phosphorylation increases in symptomatic mice overexpressing A30P alpha-synuclein. Exp Neurol 192:274–287PubMedCrossRefGoogle Scholar
  20. Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee VM (2002) Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron 34:521–533PubMedCrossRefGoogle Scholar
  21. Gispert S, Del Turco D, Garrett L, Chen A, Bernard DJ, Hamm-Clement J, Korf HW, Deller T, Braak H, Auburger G, Nussbaum RL (2003) Transgenic mice expressing mutant A53T human alpha-synuclein show neuronal dysfunction in the absence of aggregate formation. Mol Cell Neurosci 24:419–429PubMedCrossRefGoogle Scholar
  22. Gloeckner CJ, Kinkl N, Schumacher A, Braun RJ, O’Neill E, Meitinger T, Kolch W, Prokisch H, Ueffing M (2005) The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity. Hum Mol Genet 15:223–232PubMedCrossRefGoogle Scholar
  23. Goldberg MS, Fleming SM, Palacino JJ, Cepeda C, Lam HA, Bhatnagar A, Meloni EG, Wu N, Ackerson LC, Klapstein GJ, Gajendiran M, Roth BL, Chesselet MF, Maidment NT, Levine MS, Shen J (2003) Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J Biol Chem 278:43628–43635PubMedCrossRefGoogle Scholar
  24. Goldberg MS, Pisani A, Haburcak M, Vortherms TA, Kitada T, Costa C, Tong Y, Martella G, Tscherter A, Martins A, Bernardi G, Roth BL, Pothos EN, Calabresi P, Shen J (2005) Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial Parkinsonism-linked gene DJ-1. Neuron 45:489–496PubMedCrossRefGoogle Scholar
  25. Gomez-Isla T, Irizarry MC, Mariash A, Cheung B, Soto O, Schrump S, Sondel J, Kotilinek L, Day J, Schwarzschild MA, Cha JH, Newell K, Miller DW, Ueda K, Young AB, Hyman BT, Ashe KH (2003) Motor dysfunction and gliosis with preserved dopaminergic markers in human alpha-synuclein A30P transgenic mice. Neurobiol Aging 24:245–258PubMedCrossRefGoogle Scholar
  26. Hashimoto M, Rockenstein E, Mante M, Mallory M, Masliah E (2001) beta-Synuclein inhibits alpha-synuclein aggregation: a possible role as an anti-parkinsonian factor. Neuron 32:213–223PubMedCrossRefGoogle Scholar
  27. Hope A, Farrer M (2004) Genetics of α-synucleinopathy. In: Philipp K, Haass C (eds) Molecular mechanisms in Parkinson’s disease. Landes Bioscience, GeorgetownGoogle Scholar
  28. Itier JM, Ibanez P, Mena MA, Abbas N, Cohen-Salmon C, Bohme GA, Laville M, Pratt J, Corti O, Pradier L, Ret G, Joubert C, Periquet M, Araujo F, Negroni J, Casarejos MJ, Canals S, Solano R, Serrano A, Gallego E, Sanchez M, Denefle P, Benavides J, Tremp G, Rooney TA, Brice A, Garcia de Yebenes J (2003) Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse. Hum Mol Genet 12:2277–2291PubMedCrossRefGoogle Scholar
  29. Jensen PH, Nielsen MS, Jakes R, Dotti CG, Goedert M (1998) Binding of alpha-synuclein to brain vesicles is abolished by familial Parkinson’s disease mutation. J Biol Chem 273:26292–26294PubMedCrossRefGoogle Scholar
  30. Jeon BS, Jackson-Lewis V, Burke RE (1995) 6-Hydroxydopamine lesion of the rat substantia nigra: time course and morphology of cell death. Neurodegeneration 4:131–137PubMedCrossRefGoogle Scholar
  31. Kachergus J, Mata IF, Hulihan M, Taylor JP, Lincoln S, Aasly J, Gibson JM, Ross OA, Lynch T, Wiley J, Payami H, Nutt J, Maraganore DM, Czyzewski K, Styczynska M, Wszolek ZK, Farrer MJ, Toft M (2005) Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. Am J Hum Genet 76:672–680PubMedCrossRefGoogle Scholar
  32. Kahle PJ, Neumann M, Ozmen L, Muller V, Jacobsen H, Schindzielorz A, Okochi M, Leimer U, van Der Putten H, Probst A, Kremmer E, Kretzschmar HA, Haass C (2000) Subcellular localization of wild-type and Parkinson’s disease-associated mutant alpha -synuclein in human and transgenic mouse brain. J Neurosci 20:6365–6373PubMedGoogle Scholar
  33. Kahle PJ, Neumann M, Ozmen L, Muller V, Odoy S, Okamoto N, Jacobsen H, Iwatsubo T, Trojanowski JQ, Takahashi H, Wakabayashi K, Bogdanovic N, Riederer P, Kretzschmar HA, Haass C (2001) Selective insolubility of alpha-synuclein in human Lewy body diseases is recapitulated in a transgenic mouse model. Am J Pathol 159:2215–2225PubMedGoogle Scholar
  34. Kay DM, Kramer P, Higgins D, Zabetian CP, Payami H (2005) Escaping Parkinson’s disease: a neurologically healthy octogenarian with the LRRK2 G2019S mutation. Mov Disord 20:1077–1078PubMedCrossRefGoogle Scholar
  35. Khan NL, Brooks DJ, Pavese N, Sweeney MG, Wood NW, Lees AJ, Piccini P (2002) Progression of nigrostriatal dysfunction in a parkin kindred: an [18F]dopa PET and clinical study. Brain 125:2248–2256PubMedCrossRefGoogle Scholar
  36. Khan NL, Scherfler C, Graham E, Bhatia KP, Quinn N, Lees AJ, Brooks DJ, Wood NW, Piccini P (2005) Dopaminergic dysfunction in unrelated, asymptomatic carriers of a single parkin mutation. Neurology 64:134–136PubMedGoogle Scholar
  37. Kholodilov NG, Oo TF, Burke RE (1999) Synuclein expression is decreased in rat substantia nigra following induction of apoptosis by intrastriatal 6-hydroxydopamine. Neurosci Lett 275:105–108PubMedCrossRefGoogle Scholar
  38. Kim RH, Smith PD, Aleyasin H, Hayley S, Mount MP, Pownall S, Wakeham A, You-Ten AJ, Kalia SK, Horne P, Westaway D, Lozano AM, Anisman H, Park DS, Mak TW (2005) Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress. Proc Natl Acad Sci USA 102:5215–5220PubMedCrossRefGoogle Scholar
  39. Kirik D, Rosenblad C, Burger C, Lundberg C, Johansen TE, Muzyczka N, Mandel RJ, Bjorklund A (2002) Parkinson-like neurodegeneration induced by targeted overexpression of alpha-synuclein in the nigrostriatal system. J Neurosci 22:2780–2791PubMedGoogle Scholar
  40. Kirik D, Annett LE, Burger C, Muzyczka N, Mandel RJ, Bjorklund A (2003) Nigrostriatal alpha-synucleinopathy induced by viral vector-mediated overexpression of human alpha-synuclein: a new primate model of Parkinson’s disease. Proc Natl Acad Sci USA 100:2884–2889PubMedCrossRefGoogle Scholar
  41. Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605–608PubMedCrossRefGoogle Scholar
  42. Klein RL, King MA, Hamby ME, Meyer EM (2002) Dopaminergic cell loss induced by human A30P alpha-synuclein gene transfer to the rat substantia nigra. Hum Gene Ther 13:605–612PubMedCrossRefGoogle Scholar
  43. Klivenyi P, Siwek D, Gardian G, Yang L, Starkov A, Cleren C, Ferrante RJ, Kowall NW, Abeliovich A, Beal MF (2005) Mice lacking alpha-synuclein are resistant to mitochondrial toxins. Neurobiol Dis 21:541–548. DOI 10.1016/j.nbd.2005.08.018Google Scholar
  44. Kopin IJ, Markey SP (1988) MPTP toxicity: implications for research in Parkinson’s disease. Annu Rev Neurosci 11:81–96PubMedCrossRefGoogle Scholar
  45. Langston JW, Ballard P, Tetrud JW, Irwin I (1983) Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219:979–980PubMedCrossRefGoogle Scholar
  46. Lauwers E, Debyser Z, Van Dorpe J, De Strooper B, Nuttin B, Baekelandt V (2003) Neuropathology and neurodegeneration in rodent brain induced by lentiviral vector-mediated overexpression of alpha-synuclein. Brain Pathol. 13:364–372PubMedCrossRefGoogle Scholar
  47. Lee MK, Stirling W, Xu Y, Xu X, Qui D, Mandir AS, Dawson TM, Copeland NG, Jenkins NA, Price DL (2002) Human alpha-synuclein-harboring familial Parkinson’s disease-linked Ala-53 –> Thr mutation causes neurodegenerative disease with alpha-synuclein aggregation in transgenic mice. Proc Natl Acad Sci USA 99:8968–8973PubMedCrossRefGoogle Scholar
  48. Lincoln S, Wiley J, Lynch T, Langston JW, Chen R, Lang A, Rogaeva E, Sa DS, Munhoz RP, Harris J, Marder K, Klein C, Bisceglio G, Hussey J, West A, Hulihan M, Hardy J, Farrer M (2003) Parkin-proven disease: common founders but divergent phenotypes. Neurology 60:1605–1610PubMedCrossRefGoogle Scholar
  49. Lo Bianco C, Ridet JL, Schneider BL, Deglon N, Aebischer P (2002) alpha -Synucleinopathy and selective dopaminergic neuron loss in a rat lentiviral-based model of Parkinson’s disease. Proc Natl Acad Sci USA 99:10813–10818PubMedCrossRefGoogle Scholar
  50. Lockhart PJ, O’Farrell CA, Farrer MJ (2004) It’s a double knock-out! The quaking mouse is a spontaneous deletion of parkin and parkin co-regulated gene (PACRG). Mov Disord 19:101–104PubMedCrossRefGoogle Scholar
  51. Lorenzetti D, Antalffy B, Vogel H, Noveroske J, Armstrong D, Justice M (2004) The neurological mutant quaking(viable) is Parkin deficient. Mamm Genome. 15:210–217PubMedCrossRefGoogle Scholar
  52. Lo Bioanco C, Schneider BL, Bauer M, Sajadi A, Brice A, Iwatsubo T, Aebischer P (2004) Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an alpha-synuclein rat model of Parkinson’s disease. Proc Natl Acad Sci USA 101:17510–17515CrossRefGoogle Scholar
  53. Manning-Bog AB, McCormack AL, Li J, Uversky VN, Fink AL, Di Monte DA (2002) The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein. J Biol Chem 277:1641–1644PubMedCrossRefGoogle Scholar
  54. Martin LJ, Pan Y, Price AC, Sterling W, Copeland NG, Jenkins NA, Price DL, Lee MK (2006) Parkinson’s disease alpha-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death. J Neurosci 26:41–50PubMedCrossRefGoogle Scholar
  55. Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A, Sagara Y, Sisk A, Mucke L (2000) Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science 287:1265–1269PubMedCrossRefGoogle Scholar
  56. Masliah E, Rockenstein E, Veinbergs I, Sagara Y, Mallory M, Hashimoto M, Mucke L (2001) Beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer’s disease and Parkinson’s disease. Proc Natl Acad Sci USA 98:12245–12250PubMedCrossRefGoogle Scholar
  57. Mata IF, Kachergus JM, Taylor JP, Lincoln S, Aasly J, Lynch T, Hulihan MM, Cobb SA, Wu RM, Lu CS, Lahoz C, Wszolek ZK, Farrer MJ (2005) LRRK2 pathogenic substitutions in Parkinson’s disease. Neurogenetics 6:171–177PubMedCrossRefGoogle Scholar
  58. Mata IF, Lockhart PJ, Farrer MJ (2004) Parkin genetics: one model for Parkinson’s disease. Hum Mol Genet 13(1):R127–R133PubMedCrossRefGoogle Scholar
  59. Matsuoka Y, Vila M, Lincoln S, McCormack A, Picciano M, LaFrancois J, Yu X, Dickson D, Langston WJ, McGowan E, Farrer M, Hardy J, Duff K, Przedborski S, Di Monte DA (2001) Lack of nigral pathology in transgenic mice expressing human alpha-synuclein driven by the tyrosine hydroxylase promoter. Neurobiol Dis 8:535–539PubMedCrossRefGoogle Scholar
  60. McNaught KS, Perl DP, Brownell AL, Olanow CW (2004) Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson’s disease. Ann Neurol 56:149–162PubMedCrossRefGoogle Scholar
  61. Melrose HL, Lincoln S, Tyndall G, Dickson D, Farrer M (2006) Anatomical localization of LRRK2 in mouse brain. Neuroscience (in press)Google Scholar
  62. Moore DJ, West AB, Dawson VL, Dawson TM (2005) Molecular pathophysiology of Parkinson’s disease. Annu Rev Neurosci 28:57–87PubMedCrossRefGoogle Scholar
  63. Nieto M, Gil-Bea FJ, Dalfo E, Cuadrado M, Cabodevilla F, Sanchez B, Catena S, Sesma T, Ribe E, Ferrer I, Ramirez MJ, Gomez-Isla T (2005) Increased sensitivity to MPTP in human alpha-synuclein A30P transgenic mice. Neurobiol Aging 7:7. DOI 10.1016/j.neurobiolaging.2005.04.010Google Scholar
  64. Parkkinen L, Kauppinen T, Pirttila T, Autere JM, Alafuzoff I (2005) Alpha-synuclein pathology does not predict extrapyramidal symptoms or dementia. Ann Neurol 57:82–91PubMedCrossRefGoogle Scholar
  65. Perez FA, Palmiter RD (2005) Parkin-deficient mice are not a robust model of parkinsonism. Proc Natl Acad Sci USA 102:2174–2179PubMedCrossRefGoogle Scholar
  66. Perez FA, Curtis WR, Palmiter RD (2005) Parkin-deficient mice are not more sensitive to 6-hydroxydopamine or methamphetamine neurotoxicity. BMC Neurosci 6:71PubMedCrossRefGoogle Scholar
  67. Periquet M, Corti O, Jacquier S, Brice A (2005) Proteomic analysis of parkin knockout mice: alterations in energy metabolism, protein handling and synaptic function. J Neurochem 95:1259–1276PubMedCrossRefGoogle Scholar
  68. Pramstaller PP, Schlossmacher MG, Jacques TS, Scaravilli F, Eskelson C, Pepivani I, Hedrich K, Adel S, Gonzales-McNeal M, Hilker R, Kramer PL, Klein C (2005) Lewy body Parkinson’s disease in a large pedigree with 77 Parkin mutation carriers. Ann Neurol 58:411–422PubMedCrossRefGoogle Scholar
  69. Purisai MG, McCormack AL, Langston WJ, Johnston LC, Di Monte DA (2005) Alpha-synuclein expression in the substantia nigra of MPTP-lesioned non-human primates. Neurobiol Dis 20:898–906PubMedCrossRefGoogle Scholar
  70. van der Putten H, Wiederhold KH, Probst A, Barbieri S, Mistl C, Danner S, Kauffmann S., Hofele K, Spooren WP, Ruegg MA, Lin S, Caroni P, Sommer B, Tolnay M, Bilbe G (2000) Neuropathology in mice expressing human alpha-synuclein. J Neurosci 20:6021–6029PubMedGoogle Scholar
  71. Richardson JR, Quan Y, Sherer TB, Greenamyre JT, Miller GW (2005) Paraquat neurotoxicity is distinct from that of MPTP and rotenone. Toxicol Sci 88:193–201PubMedCrossRefGoogle Scholar
  72. Richfield EK, Thiruchelvam MJ, Cory-Slechta DA, Wuertzer C, Gainetdinov RR, Caron MG, Di Monte DA, Federoff HJ (2002) Behavioral and neurochemical effects of wild-type and mutated human alpha-synuclein in transgenic mice. Exp Neurol 175:35–48PubMedCrossRefGoogle Scholar
  73. Robertson DC, Schmidt O, Ninkina N, Jones PA, Sharkey J, Buchman VL (2004) Developmental loss and resistance to MPTP toxicity of dopaminergic neurones in substantia nigra pars compacta of gamma-synuclein, alpha-synuclein and double alpha/gamma-synuclein null mutant mice. J Neurochem 89:1126–1136PubMedCrossRefGoogle Scholar
  74. Rockenstein E, Mallory M, Hashimoto M, Song D, Shults CW, Lang I, Masliah E (2002). Differential neuropathological alterations in transgenic mice expressing alpha-synuclein from the platelet-derived growth factor and Thy-1 promoters. J Neurosci Res 68:568–578PubMedCrossRefGoogle Scholar
  75. Ross OA, Farrer MJ (2005) Pathophysiology, pleiotrophy and paradigm shifts: genetic lessons from Parkinson’s disease. Biochem Soc Trans 33:586–590PubMedCrossRefGoogle Scholar
  76. Ross OA, Toft M, Whittle AJ, Johnson JL, Papapetropoulos S, Mash DC, Litvan I, Gordon MF, Wszolek ZK, Farrer MJ, Dickson DW (2006) LRRK2 and Lewy body disease. Ann Neurol 59:388–393PubMedCrossRefGoogle Scholar
  77. Schluter OM, Fornai F, Alessandri MG, Takamori S, Geppert M, Jahn R, Sudhof TC (2003) Role of alpha-synuclein in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice. Neuroscience 118:985–1002PubMedCrossRefGoogle Scholar
  78. Schober A (2004) Classic toxin-induced animal models of Parkinson’s disease: 6-OHDA and MPTP. Cell Tissue Res 318:215–224PubMedCrossRefGoogle Scholar
  79. Sedelis M, Schwarting RK, Huston JP (2001) Behavioral phenotyping of the MPTP mouse model of Parkinson’s disease. Behav Brain Res 125:109–125PubMedCrossRefGoogle Scholar
  80. Sherer TB, Betarbet R, Greenamyre JT (2002) Environment, mitochondria, and Parkinson’s disease. Neuroscientist 8:192–197PubMedGoogle Scholar
  81. Sherer TB, Kim JH, Betarbet R, Greenamyre JT (2003) Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and alpha-synuclein aggregation. Exp Neurol 179:9–16PubMedCrossRefGoogle Scholar
  82. Simon-Sanchez J, Herranz-Perez V, Olucha-Bordonau F, Perez-Tur J (2006) LRRK2 is expressed in areas affected by Parkinson’s disease in the adult mouse brain. Eur J Neurosci 23:659–666PubMedCrossRefGoogle Scholar
  83. Song DD, Shults CW, Sisk A, Rockenstein E, Masliah E (2004) Enhanced substantia nigra mitochondrial pathology in human alpha-synuclein transgenic mice after treatment with MPTP. Exp Neurol 186:158–172PubMedCrossRefGoogle Scholar
  84. Sopher BL, La Spada AR (2006) Efficient recombination-based methods for bacterial artificial chromosome fusion and mutagenesis. Gene 15:15Google Scholar
  85. Specht CG, Schoepfer R (2001) Deletion of the alpha-synuclein locus in a subpopulation of C57BL/6J inbred mice. BMC Neurosci 2:24CrossRefGoogle Scholar
  86. Speciale SG (2002) MPTP: insights into parkinsonian neurodegeneration. Neurotoxicol Teratol 24:607–620PubMedCrossRefGoogle Scholar
  87. Steidl JV, Gomez-Isla T, Mariash A, Ashe KH, Boland LM (2003) Altered short-term hippocampal synaptic plasticity in mutant alpha-synuclein transgenic mice. Neuroreport 14:219–223PubMedCrossRefGoogle Scholar
  88. Tao X, Tong L (2003) Crystal structure of human DJ-1, a protein associated with early onset Parkinson’s disease. J Biol Chem 278:31372–31379PubMedCrossRefGoogle Scholar
  89. Twelves D, Perkins KS, Counsell C (2003) Systematic review of incidence studies of Parkinson’s disease. Mov Disord 18:19–31PubMedCrossRefGoogle Scholar
  90. Vila M, Vukosavic S, Jackson-Lewis V, Neystat M, Jakowec M, Przedborski S (2000) Alpha-synuclein up-regulation in substantia nigra dopaminergic neurons following administration of the parkinsonian toxin MPTP. J Neurochem 74:721–729PubMedCrossRefGoogle Scholar
  91. Von Coelln R, Thomas B, Savitt JM, Lim KL, Sasaki M, Hess EJ, Dawson VL, Dawson TM (2004) Loss of locus coeruleus neurons and reduced startle in parkin null mice. Proc Natl Acad Sci USA 101:10744–10749CrossRefGoogle Scholar
  92. Watanabe Y, Himeda T, Araki T (2005) Mechanisms of MPTP toxicity and their implications for therapy of Parkinson’s disease. Med Sci Monit 11:RA17–RA23PubMedGoogle Scholar
  93. West A, Periquet M, Lincoln S, Lucking CB, Nicholl D, Bonifati V, Rawal N, Gasser T, Lohmann E, Deleuze JF, Maraganore D, Levey A, Wood N, Durr A, Hardy J, Brice A, Farrer M (2002) Complex relationship between Parkin mutations and Parkinson disease. Am J Med Genet 114:584–591PubMedCrossRefGoogle Scholar
  94. West AB, Moore DJ, Biskup S, Bugayenko A, Smith WW, Ross CA, Dawson VL, Dawson TM (2005) Parkinson’s disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci USA 102:16842–16847PubMedCrossRefGoogle Scholar
  95. Yamada M, Iwatsubo T, Mizuno Y, Mochizuki H (2004) Overexpression of alpha-synuclein in rat substantia nigra results in loss of dopaminergic neurons, phosphorylation of alpha-synuclein and activation of caspase-9: resemblance to pathogenetic changes in Parkinson’s disease. J Neurochem 91:451–461PubMedCrossRefGoogle Scholar
  96. Yamada M, Mizuno Y, Mochizuki H (2005) Parkin gene therapy for alpha-synucleinopathy: a rat model of Parkinson’s disease. Hum Gene Ther 16:262–270PubMedCrossRefGoogle Scholar
  97. Zeng BY, Dass B, Owen A, Rose S, Cannizzaro C, Tel BC, Jenner P, Kholodilov NG, Oo TF, Burke RE (2002) 6-Hydroxydopamine lesioning differentially affects alpha-synuclein mRNA expression in the nucleus accumbens, striatum and substantia nigra of adult ratsGoogle Scholar
  98. Zhang L, Shimoji M, Thomas B, Moore DJ, Yu SW, Marupudi NI, Torp R, Torgner IA, Ottersen OP, Dawson TM, Dawson VL (2005) Mitochondrial localization of the Parkinson’s disease related protein DJ-1: implications for pathogenesis. Hum Mol Genet 14:2063–2073PubMedCrossRefGoogle Scholar
  99. Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, Kachergus J, Hulihan M, Uitti RJ, Calne DB, Stoessl AJ, Pfeiffer RF, Patenge N, Carbajal IC, Vieregge P, Asmus F, Muller-Myhsok B, Dickson DW, Meitinger T, Strom TM, Wszolek ZK, Gasser T (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44:601–607PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Heather L. Melrose
    • 1
  • Sarah J. Lincoln
    • 1
  • Glenn M. Tyndall
    • 1
  • Matthew J. Farrer
    • 1
  1. 1.Department of Neuroscience, Genetics of Parkinsonism and Related DisordersMorris K. Udall Parkinson’s Disease Research Center of Excellence, Birdsall Bldg., Mayo ClinicJacksonvilleUSA

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