Advertisement

Animal Models for PD and ALS

  • Max V. Kuenstling
  • Adam M. Szlachetka
  • R. Lee Mosley
Protocol
Part of the Springer Protocols Handbooks book series (SPH)

Abstract

Current research into neurodegenerative disorders relies heavily on animal models that recapitulate human disease. This chapter focuses on genetic and toxin-based animal models of Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS). Early models failed to duplicate many of the hallmarks of these diseases, such as the loss of dopaminergic neurons in PD and motor neuron loss in ALS, and were often dismissed as newer models were developed. Nevertheless, even current models may not fully mimic all facets of disease etiology, progression, or pathology, necessitating continued research into developing models that more closely replicate the clinical manifestations of the disease. For both PD and ALS, genetic models have been generated based on the clinical reports of familial forms of the disease. For PD, models have been created using genes coding for α-synuclein, parkin, LRRK2, DJ-1, and PINK1, while mutations in genes coding for SOD1, FUS/TLS, and TDP-43 have been used for ALS models. For either disease, fewer than 10 % of all cases are linked to genetic causes, whereas the majority of cases are termed sporadic and are likely caused by environmental factors or a combination of environmental factors and genetically imposed susceptibilities. Therefore, a large number of animal models are toxin-based, utilizing chemicals or metals that have been correlated with human disease. As a whole, current animal models serve as adequate substitutes to their human counterparts, providing valuable tools for translational and basic science research in PD and ALS, with the caveat that most models typically do not recapitulate the totality of the human disease. Therefore, this chapter intends to describe the more commonly used animal models for these diseases and relate their limitations.

Keywords

Parkinson’s disease Amyotrophic lateral sclerosis Animal models α-Synuclein LRRK2 Parkin 6-OHDA MPTP SOD1 FUS/TLS TDP-43 

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. Adams CR, Ziegler DK, Lin JT (1983) Mercury intoxication simulating amyotrophic lateral sclerosis. JAMA 250:642–643PubMedCrossRefGoogle Scholar
  3. Alexander GM, Erwin KL, Byers N, Deitch JS, Augelli BJ, Blankenhorn EP, Heiman-Patterson TD (2004) Effect of transgene copy number on survival in the G93A SOD1 transgenic mouse model of ALS. Brain Res Mol Brain Res 130:7–15PubMedCrossRefGoogle Scholar
  4. Anderson G, Noorian AR, Taylor G, Anitha M, Bernhard D, Srinivasan S, Greene JG (2007) Loss of enteric dopaminergic neurons and associated changes in colon motility in an MPTP mouse model of Parkinson’s disease. Exp Neurol 207:4–12PubMedPubMedCentralCrossRefGoogle Scholar
  5. Andres-Mateos E, Perier C, Zhang L, Blanchard-Fillion B, Greco TM, Thomas B, Ko HS, Sasaki M, Ischiropoulos H, Przedborski S, Dawson TM, Dawson VL (2007) DJ-1 gene deletion reveals that DJ-1 is an atypical peroxiredoxin-like peroxidase. Proc Natl Acad Sci U S A 104:14807–14812PubMedPubMedCentralCrossRefGoogle Scholar
  6. Andres-Mateos E, Mejias R, Sasaki M, Li X, Lin BM, Biskup S, Zhang L, Banerjee R, Thomas B, Yang L, Liu G, Beal MF, Huso DL, Dawson TM, Dawson VL (2009) Unexpected lack of hypersensitivity in LRRK2 knock-out mice to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). J Neurosci 29:15846–15850PubMedPubMedCentralCrossRefGoogle Scholar
  7. Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, Mann D, Tsuchiya K, Yoshida M, Hashizume Y, Oda T (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351:602–611PubMedCrossRefGoogle Scholar
  8. Arvidson B (1992) Accumulation of inorganic mercury in lower motoneurons of mice. Neurotoxicology 13:277–280PubMedGoogle Scholar
  9. Ascherio A, Chen H, Weisskopf MG, O’Reilly E, McCullough ML, Calle EE, Schwarzschild MA, Thun MJ (2006) Pesticide exposure and risk for Parkinson’s disease. Ann Neurol 60:197–203PubMedCrossRefGoogle Scholar
  10. Backman CM, Malik N, Zhang Y, Shan L, Grinberg A, Hoffer BJ, Westphal H, Tomac AC (2006) Characterization of a mouse strain expressing Cre recombinase from the 3′ untranslated region of the dopamine transporter locus. Genesis 44:383–390PubMedCrossRefGoogle Scholar
  11. Banks GT, Kuta A, Isaacs AM, Fisher EM (2008) TDP-43 is a culprit in human neurodegeneration, and not just an innocent bystander. Mamm Genome 19:299–305PubMedPubMedCentralCrossRefGoogle Scholar
  12. Barber TE (1978) Inorganic mercury intoxication reminiscent of amyotrophic lateral sclerosis. J Occup Med 20:667–669PubMedGoogle Scholar
  13. Bartels T, Choi JG, Selkoe DJ (2011) Alpha-synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature 477:107–110PubMedPubMedCentralCrossRefGoogle Scholar
  14. Benner EJ, Mosley RL, Destache CJ, Lewis TB, Jackson-Lewis V, Gorantla S, Nemachek C, Green SR, Przedborski S, Gendelman HE (2004) Therapeutic immunization protects dopaminergic neurons in a mouse model of Parkinson’s disease. Proc Natl Acad Sci U S A 101:9435–9440PubMedPubMedCentralCrossRefGoogle Scholar
  15. Benner EJ, Banerjee R, Reynolds AD, Sherman S, Pisarev VM, Tsiperson V, Nemachek C, Ciborowski P, Przedborski S, Mosley RL, Gendelman HE (2008) Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergic neurons. PLoS One 3:e1376PubMedPubMedCentralCrossRefGoogle Scholar
  16. Berger K, Przedborski S, Cadet JL (1991) Retrograde degeneration of nigrostriatal neurons induced by intrastriatal 6-hydroxydopamine injection in rats. Brain Res Bull 26:301–307PubMedCrossRefGoogle Scholar
  17. Bergman H, Wichmann T, DeLong MR (1990) Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science 249:1436–1438PubMedCrossRefGoogle Scholar
  18. 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
  19. Biskup S, Moore DJ, Celsi F, Higashi S, West AB, Andrabi SA, Kurkinen K, Yu SW, Savitt JM, Waldvogel HJ, Faull RL, Emson PC, Torp R, Ottersen OP, Dawson TM, Dawson VL (2006) Localization of LRRK2 to membranous and vesicular structures in mammalian brain. Ann Neurol 60:557–569PubMedCrossRefGoogle Scholar
  20. Bjorklund LM, Sanchez-Pernaute R, Chung S, Andersson T, Chen IY, McNaught KS, Brownell AL, Jenkins BG, Wahlestedt C, Kim KS, Isacson O (2002) Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc Natl Acad Sci U S A 99:2344–2349PubMedPubMedCentralCrossRefGoogle Scholar
  21. Boillee S, Yamanaka K, Lobsiger CS, Copeland NG, Jenkins NA, Kassiotis G, Kollias G, Cleveland DW (2006) Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312:1389–1392PubMedCrossRefGoogle Scholar
  22. 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
  23. Bonifati V, Oostra BA, Heutink P (2004) Linking DJ-1 to neurodegeneration offers novel insights for understanding the pathogenesis of Parkinson’s disease. J Mol Med (Berl) 82:163–174CrossRefGoogle Scholar
  24. Boska MD, Lewis TB, Destache CJ, Benner EJ, Nelson JA, Uberti M, Mosley RL, Gendelman HE (2005) Quantitative 1H magnetic resonance spectroscopic imaging determines therapeutic immunization efficacy in an animal model of Parkinson’s disease. J Neurosci 25:1691–1700PubMedCrossRefGoogle Scholar
  25. Boska MD, Hasan KM, Kibuule D, Banerjee R, McIntyre E, Nelson JA, Hahn T, Gendelman HE, Mosley RL (2007) Quantitative diffusion tensor imaging detects dopaminergic neuronal degeneration in a murine model of Parkinson’s disease. Neurobiol Dis 26: 590–596PubMedPubMedCentralCrossRefGoogle Scholar
  26. Bove J, Prou D, Perier C, Przedborski S (2005) Toxin-induced models of Parkinson’s disease. NeuroRx 2:484–494PubMedPubMedCentralCrossRefGoogle Scholar
  27. Brochard V, Combadiere B, Prigent A, Laouar Y, Perrin A, Beray-Berthat V, Bonduelle O, Alvarez-Fischer D, Callebert J, Launay JM, Duyckaerts C, Flavell RA, Hirsch EC, Hunot S (2009) Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Invest 119:182–192PubMedGoogle Scholar
  28. Brooks AI, Chadwick CA, Gelbard HA, Cory-Slechta DA, Federoff HJ (1999) Paraquat elicited neurobehavioral syndrome caused by dopaminergic neuron loss. Brain Res 823:1–10PubMedCrossRefGoogle Scholar
  29. Buratti E, Baralle FE (2008) Multiple roles of TDP-43 in gene expression, splicing regulation, and human disease. Front Biosci 13:867–878PubMedCrossRefGoogle Scholar
  30. Castano A, Herrera AJ, Cano J, Machado A (1998) Lipopolysaccharide intranigral injection induces inflammatory reaction and damage in nigrostriatal dopaminergic system. J Neurochem 70:1584–1592PubMedCrossRefGoogle Scholar
  31. Chai A, Withers J, Koh YH, Parry K, Bao H, Zhang B, Budnik V, Pennetta G (2008) HVAPB, the causative gene of a heterogeneous group of motor neuron diseases in humans, is functionally interchangeable with its Drosophila homologue DVAP-33A at the neuromuscular junction. Hum Mol Genet 17:266–280PubMedCrossRefGoogle Scholar
  32. Chan P, DeLanney LE, Irwin I, Langston JW, Di Monte D (1991) Rapid ATP loss caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mouse brain. J Neurochem 57:348–351PubMedCrossRefGoogle Scholar
  33. Chan P, Tanner CM, Jiang X, Langston JW (1998) Failure to find the alpha-synuclein gene missense mutation (G209A) in 100 patients with younger onset Parkinson’s disease. Neurology 50:513–514PubMedCrossRefGoogle Scholar
  34. Chen Y, Yang M, Deng J, Chen X, Ye Y, Zhu L, Liu J, Ye H, Shen Y, Li Y, Rao EJ, Fushimi K, Zhou X, Bigio EH, Mesulam M, Xu Q, Wu JY (2011) Expression of human FUS protein in Drosophila leads to progressive neurodegeneration. Protein Cell 2:477–486PubMedPubMedCentralCrossRefGoogle Scholar
  35. Choi J, Sullards MC, Olzmann JA, Rees HD, Weintraub ST, Bostwick DE, Gearing M, Levey AI, Chin LS, Li L (2006) Oxidative damage of DJ-1 is linked to sporadic Parkinson and Alzheimer diseases. J Biol Chem 281:10816–10824PubMedPubMedCentralCrossRefGoogle Scholar
  36. Clark AW, Griffin JW, Price DL (1980) The axonal pathology in chronic IDPN intoxication. J Neuropathol Exp Neurol 39:42–55PubMedCrossRefGoogle Scholar
  37. Clark IE, Dodson MW, Jiang C, Cao JH, Huh JR, Seol JH, Yoo SJ, Hay BA, Guo M (2006) Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 441:1162–1166PubMedCrossRefGoogle Scholar
  38. Cohen G, Werner P (1994) Free radicals, oxidative stress, and neurodegeneration. In: Calne DB (ed) Neurodegenerative diseases. W.B. Saunders, Philadelphia, pp 139–161Google Scholar
  39. Combault M (1880) Contribution a l’etude anatomique de la n’evite parenchymateuse subaigue et chronique: n’evite segmentaire p’eri-axile. Arch Neurol (Paris) 1:11–38Google Scholar
  40. Conradi S, Ronnevi LO, Narris FH (1982) Motor neuron disease and toxic metals. In: Rowland LP (ed) Human motor neuron disease. Raven, New York, pp 201–231Google Scholar
  41. Cook SA, Johnson KR, Bronson RT, Davisson MT (1995) Neuromuscular degeneration (nmd): a mutation on mouse chromosome 19 that causes motor neuron degeneration. Mamm Genome 6:187–191PubMedCrossRefGoogle Scholar
  42. Cookson MR (2005) The biochemistry of Parkinson’s disease. Annu Rev Biochem 74:29–52PubMedCrossRefGoogle Scholar
  43. Dammann O, Leviton A (1997) Does prepregnancy bacterial vaginosis increase a mother’s risk of having a preterm infant with cerebral palsy? Dev Med Child Neurol 39:836–840PubMedCrossRefGoogle Scholar
  44. Davis GC, Williams AC, Markey SP, Ebert MH, Caine ED, Reichert CM, Kopin IJ (1979) Chronic parkinsonism secondary to intravenous injection of meperidine analogues. Psychiatry Res 1:249–254PubMedCrossRefGoogle Scholar
  45. Day BJ, Patel M, Calavetta L, Chang LY, Stamler JS (1999) A mechanism of paraquat toxicity involving nitric oxide synthase. Proc Natl Acad Sci U S A 96:12760–12765PubMedPubMedCentralCrossRefGoogle Scholar
  46. Di Monte D, Sandy MS, Ekstrom G, Smith MT (1986) Comparative studies on the mechanisms of paraquat and 1-methyl-4-phenylpyridine (MPP+) cytotoxicity. Biochem Biophys Res Commun 137:303–309PubMedCrossRefGoogle Scholar
  47. Drolet RE, Cannon JR, Montero L, Greenamyre JT (2009) Chronic rotenone exposure reproduces Parkinson’s disease gastrointestinal neuropathology. Neurobiol Dis 36:96–102PubMedCrossRefGoogle Scholar
  48. Duchen LW, Strich SJ (1968) An hereditary motor neurone disease with progressive denervation of muscle in the mouse: the mutant ‘wobbler’. J Neurol Neurosurg Psychiatry 31:535–542PubMedPubMedCentralCrossRefGoogle Scholar
  49. Ekstrand MI, Galter D (2009) The MitoPark mouse—an animal model of Parkinson’s disease with impaired respiratory chain function in dopamine neurons. Parkinsonism Relat Disord 15(suppl 3):S185–S188PubMedCrossRefGoogle Scholar
  50. Ekstrand MI, Terzioglu M, Galter D, Zhu S, Hofstetter C, Lindqvist E, Thams S, Bergstrand A, Hansson FS, Trifunovic A, Hoffer B, Cullheim S, Mohammed AH, Olson L, Larsson NG (2007) Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons. Proc Natl Acad Sci U S A 104:1325–1330PubMedPubMedCentralCrossRefGoogle Scholar
  51. Fabre E, Monserrat J, Herrero A, Barja G, Leret ML (1999) Effect of MPTP on brain mitochondrial H2O2 and ATP production and on dopamine and DOPAC in the striatum. J Physiol Biochem 55:325–331PubMedGoogle Scholar
  52. Farrer M, Maraganore DM, Lockhart P, Singleton A, Lesnick TG, de Andrade M, West A, de Silva R, Hardy J, Hernandez D (2001) Alpha-synuclein gene haplotypes are associated with Parkinson’s disease. Hum Mol Genet 10:1847–1851PubMedCrossRefGoogle Scholar
  53. Feany MB, Bender WW (2000) A Drosophila model of Parkinson’s disease. Nature 404:394–398PubMedCrossRefGoogle Scholar
  54. Ferrante RJ, Schulz JB, Kowall NW, Beal MF (1997) Systemic administration of rotenone produces selective damage in the striatum and globus pallidus, but not in the substantia nigra. Brain Res 753:157–162PubMedCrossRefGoogle Scholar
  55. Ferraz HB, Bertolucci PH, Pereira JS, Lima JG, Andrade LA (1988) Chronic exposure to the fungicide maneb may produce symptoms and signs of CNS manganese intoxication. Neurology 38:550–553PubMedCrossRefGoogle Scholar
  56. Fleming SM, Fernagut PO, Chesselet MF (2005) Genetic mouse models of parkinsonism: strengths and limitations. NeuroRx 2:495–503PubMedPubMedCentralCrossRefGoogle Scholar
  57. Fornai F, Schluter OM, Lenzi P, Gesi M, Ruffoli R, Ferrucci M, Lazzeri G, Busceti CL, Pontarelli F, Battaglia G, Pellegrini A, Nicoletti F, Ruggieri S, Paparelli A, Sudhof TC (2005) Parkinson-like syndrome induced by continuous MPTP infusion: convergent roles of the ubiquitin-proteasome system and alpha-synuclein. Proc Natl Acad Sci U S A 102: 3413–3418PubMedPubMedCentralCrossRefGoogle Scholar
  58. Forno LS, DeLanney LE, Irwin I, Langston JW (1993) Similarities and differences between MPTP-induced parkinsonism and Parkinson’s disease. Neuropathologic considerations. Adv Neurol 60:600–608PubMedGoogle Scholar
  59. Galter D, Westerlund M, Carmine A, Lindqvist E, Sydow O, Olson L (2006) LRRK2 expression linked to dopamine-innervated areas. Ann Neurol 59:714–719PubMedCrossRefGoogle Scholar
  60. Gandhi S, Muqit MM, Stanyer L, Healy DG, Abou-Sleiman PM, Hargreaves I, Heales S, Ganguly M, Parsons L, Lees AJ, Latchman DS, Holton JL, Wood NW, Revesz T (2006) PINK1 protein in normal human brain and Parkinson’s disease. Brain 129:1720–1731PubMedCrossRefGoogle Scholar
  61. Gao HM, Jiang J, Wilson B, Zhang W, Hong JS, Liu B (2002) Microglial activation-mediated delayed and progressive degeneration of rat nigral dopaminergic neurons: relevance to Parkinson’s disease. J Neurochem 81:1285–1297PubMedCrossRefGoogle Scholar
  62. Garruto R, Yanagihara R, Gajdusek D, Arion D (1984) Concentrations of trace and essential elements in garden soil and drinking water in the Western Pacific. National Taiwan University Press, TaipeiGoogle Scholar
  63. Gasser T (2009) Molecular pathogenesis of Parkinson disease: insights from genetic studies. Expert Rev Mol Med 11:e22PubMedCrossRefGoogle Scholar
  64. Gelman DM, Noain D, Avale ME, Otero V, Low MJ, Rubinstein M (2003) Transgenic mice engineered to target Cre/loxP-mediated DNA recombination into catecholaminergic neurons. Genesis 36:196–202PubMedCrossRefGoogle Scholar
  65. George JM, Jin H, Woods WS, Clayton DF (1995) Characterization of a novel protein regulated during the critical period for song learning in the zebra finch. Neuron 15:361–372PubMedCrossRefGoogle Scholar
  66. Gilks WP, Abou-Sleiman PM, Gandhi S, Jain S, Singleton A, Lees AJ, Shaw K, Bhatia KP, Bonifati V, Quinn NP, Lynch J, Healy DG, Holton JL, Revesz T, Wood NW (2005) A common LRRK2 mutation in idiopathic Parkinson’s disease. Lancet 365:415–416PubMedGoogle Scholar
  67. Giovanni A, Sonsalla PK, Heikkila RE (1994) 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 270:1008–1014PubMedGoogle Scholar
  68. Gispert S et al (2009) Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration. PLoS One 4:e5777PubMedPubMedCentralCrossRefGoogle Scholar
  69. Gloeckner CJ, Kinkl N, Schumacher A, Braun RJ, O’Neill E, Meitinger T, Kolch W, Prokisch H, Ueffing M (2006) The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity. Hum Mol Genet 15:223–232PubMedCrossRefGoogle Scholar
  70. 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
  71. 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
  72. Gong YH, Parsadanian AS, Andreeva A, Snider WD, Elliott JL (2000) Restricted expression of G86R Cu/Zn superoxide dismutase in astrocytes results in astrocytosis but does not cause motoneuron degeneration. J Neurosci 20:660–665PubMedGoogle Scholar
  73. Gordon PH, Moore DH, Miller RG, Florence JM, Verheijde JL, Doorish C, Hilton JF, Spitalny GM, MacArthur RB, Mitsumoto H, Neville HE, Boylan K, Mozaffar T, Belsh JM, Ravits J, Bedlack RS, Graves MC, McCluskey LF, Barohn RJ, Tandan R (2007) Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol 6:1045–1053PubMedCrossRefGoogle Scholar
  74. Greene JC, Whitworth AJ, Kuo I, Andrews LA, Feany MB, Pallanck LJ (2003) Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc Natl Acad Sci U S A 100:4078–4083PubMedPubMedCentralCrossRefGoogle Scholar
  75. Griffin J, Price D (1980) Proximal axonopathies induced by toxic chemicals. In: Spencer P, Schaumburg H (eds) Experimental and clinical neurotoxicology. Williams and Wilkins, Baltimore, pp 161–178Google Scholar
  76. Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, Caliendo J, Hentati A, Kwon YW, Deng HX et al (1994) Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science 264:1772–1775PubMedCrossRefGoogle Scholar
  77. Hasegawa E, Takeshige K, Oishi T, Murai Y, Minakami S (1990) 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 170:1049–1055PubMedCrossRefGoogle Scholar
  78. Hasegawa E, Kang D, Sakamoto K, Mitsumoto A, Nagano T, Minakami S, Takeshige K (1997) A dual effect of 1-methyl-4-phenylpyridinium (MPP+)-analogs on the respiratory chain of bovine heart mitochondria. Arch Biochem Biophys 337:69–74PubMedCrossRefGoogle Scholar
  79. Hatano Y, Li Y, Sato K, Asakawa S, Yamamura Y, Tomiyama H, Yoshino H, Asahina M, Kobayashi S, Hassin-Baer S, Lu CS, Ng AR, Rosales RL, Shimizu N, Toda T, Mizuno Y, Hattori N (2004) Novel PINK1 mutations in early-onset parkinsonism. Ann Neurol 56:424–427PubMedCrossRefGoogle Scholar
  80. Healy DG et al (2008) Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case-control study. Lancet Neurol 7:583–590PubMedPubMedCentralCrossRefGoogle Scholar
  81. Heimann P, Laage S, Jockusch H (1991) Defect of sperm assembly in a neurological mutant of the mouse, wobbler (WR). Differentiation 47:77–83PubMedCrossRefGoogle Scholar
  82. Herrero MT, Hirsch EC, Kastner A, Ruberg M, Luquin MR, Laguna J, Javoy-Agid F, Obeso JA, Agid Y (1993) Does neuromelanin contribute to the vulnerability of catecholaminergic neurons in monkeys intoxicated with MPTP? Neuroscience 56:499–511PubMedCrossRefGoogle Scholar
  83. Hicks GG, Singh N, Nashabi A, Mai S, Bozek G, Klewes L, Arapovic D, White EK, Koury MJ, Oltz EM, Van Kaer L, Ruley HE (2000) Fus deficiency in mice results in defective B-lymphocyte development and activation, high levels of chromosomal instability and perinatal death. Nat Genet 24:175–179PubMedCrossRefGoogle Scholar
  84. Hoglinger GU, Feger J, Prigent A, Michel PP, Parain K, Champy P, Ruberg M, Oertel WH, Hirsch EC (2003) Chronic systemic complex I inhibition induces a hypokinetic multisystem degeneration in rats. J Neurochem 84:491–502PubMedCrossRefGoogle Scholar
  85. Hutter-Saunders JA, Mosley RL, Gendelman HE (2011) Pathways towards an effective immunotherapy for Parkinson’s disease. Expert Rev Neurother 11:1703–1715PubMedPubMedCentralCrossRefGoogle Scholar
  86. Imai Y, Gehrke S, Wang HQ, Takahashi R, Hasegawa K, Oota E, Lu B (2008) Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila. EMBO J 27:2432–2443PubMedPubMedCentralCrossRefGoogle Scholar
  87. Itier JM et al (2003) Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse. Hum Mol Genet 12:2277–2291PubMedCrossRefGoogle Scholar
  88. Jackson-Lewis V, Przedborski S (2007) Protocol for the MPTP mouse model of Parkinson’s disease. Nat Protoc 2:141–151PubMedCrossRefGoogle Scholar
  89. Javitch JA, D’Amato RJ, Strittmatter SM, Snyder SH (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 U S A 82:2173–2177PubMedPubMedCentralCrossRefGoogle Scholar
  90. Javoy F, Sotelo C, Herbet A, Agid Y (1976) Specificity of dopaminergic neuronal degeneration induced by intracerebral injection of 6-hydroxydopamine in the nigrostriatal dopamine system. Brain Res 102:201–215PubMedCrossRefGoogle Scholar
  91. 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
  92. Jensen PH, Hager H, Nielsen MS, Hojrup P, Gliemann J, Jakes R (1999) Alpha-synuclein binds to Tau and stimulates the protein kinase A-catalyzed tau phosphorylation of serine residues 262 and 356. J Biol Chem 274:25481–25489PubMedCrossRefGoogle Scholar
  93. Jensen PH, Islam K, Kenney J, Nielsen MS, Power J, Gai WP (2000) Microtubule-associated protein 1B is a component of cortical Lewy bodies and binds alpha-synuclein filaments. J Biol Chem 275:21500–21507PubMedCrossRefGoogle Scholar
  94. 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
  95. Jiang H, Jackson-Lewis V, Muthane U, Dollison A, Ferreira M, Espinosa A, Parsons B, Przedborski S (1993) Adenosine receptor antagonists potentiate dopamine receptor agonist-induced rotational behavior in 6-hydroxydopamine-lesioned rats. Brain Res 613:347–351PubMedCrossRefGoogle Scholar
  96. Jonsson G (1983) Chemical lesioning techniques: monoamine neurotoxins. In: Bjorklund A, Hokfelt T (eds) Handbook of chemical neuroanatomy. Elsevier, Amsterdam, pp 463–507Google Scholar
  97. Joyce PI, Fratta P, Fisher EM, Acevedo-Arozena A (2011) SOD1 and TDP-43 animal models of amyotrophic lateral sclerosis: recent advances in understanding disease toward the development of clinical treatments. Mamm Genome 22:420–448PubMedCrossRefGoogle Scholar
  98. Ju S, Tardiff DF, Han H, Divya K, Zhong Q, Maquat LE, Bosco DA, Hayward LJ, Brown RH Jr, Lindquist S, Ringe D, Petsko GA (2011) A yeast model of FUS/TLS-dependent cytotoxicity. PLoS Biol 9:e1001052PubMedPubMedCentralCrossRefGoogle Scholar
  99. Kahle PJ, Haass C, Kretzschmar HA, Neumann M (2002) Structure/function of alpha-synuclein in health and disease: rational development of animal models for Parkinson’s and related diseases. J Neurochem 82:449–457PubMedCrossRefGoogle Scholar
  100. Khan NL et al (2005) Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson’s disease: clinical, pathological, olfactory and functional imaging and genetic data. Brain 128:2786–2796PubMedCrossRefGoogle Scholar
  101. 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 U S A 102:5215–5220PubMedPubMedCentralCrossRefGoogle Scholar
  102. 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
  103. 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
  104. Klaidman LK, Adams JD Jr, Leung AC, Kim SS, Cadenas E (1993) Redox cycling of MPP+: evidence for a new mechanism involving hydride transfer with xanthine oxidase, aldehyde dehydrogenase, and lipoamide dehydrogenase. Free Radic Biol Med 15:169–179PubMedCrossRefGoogle Scholar
  105. 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
  106. Kopin IJ, Markey SP (1988) MPTP toxicity: implications for research in Parkinson’s disease. Annu Rev Neurosci 11:81–96PubMedCrossRefGoogle Scholar
  107. Kordower JH, Kanaan NM, Chu Y, Suresh Babu R, Stansell J III, Terpstra BT, Sortwell CE, Steece-Collier K, Collier TJ (2006) Failure of proteasome inhibitor administration to provide a model of Parkinson’s disease in rats and monkeys. Ann Neurol 60:264–268PubMedCrossRefGoogle Scholar
  108. Kosloski LM, Ha DM, Hutter JA, Stone DK, Pichler MR, Reynolds AD, Gendelman HE, Mosley RL (2010) Adaptive immune regulation of glial homeostasis as an immunization strategy for neurodegenerative diseases. J Neurochem 114:1261–1276PubMedPubMedCentralGoogle Scholar
  109. Kriz J, Nguyen MD, Julien JP (2002) Minocycline slows disease progression in a mouse model of amyotrophic lateral sclerosis. Neurobiol Dis 10:268–278PubMedCrossRefGoogle Scholar
  110. Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, Kosel S, Przuntek H, Epplen JT, Schols L, Riess O (1998) Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet 18:106–108PubMedCrossRefGoogle Scholar
  111. Kurkowska-Jastrzebska I, Wronska A, Kohutnicka M, Czlonkowski A, Czlonkowska A (1999a) The inflammatory reaction following 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine intoxication in mouse. Exp Neurol 156:50–61PubMedCrossRefGoogle Scholar
  112. Kurkowska-Jastrzebska I, Wronska A, Kohutnicka M, Czlonkowski A, Czlonkowska A (1999b) MHC class II positive microglia and lymphocytic infiltration are present in the substantia nigra and striatum in mouse model of Parkinson’s disease. Acta Neurobiol Exp (Wars) 59:1–8Google Scholar
  113. Kuwahara T, Koyama A, Gengyo-Ando K, Masuda M, Kowa H, Tsunoda M, Mitani S, Iwatsubo T (2006) Familial Parkinson mutant alpha-synuclein causes dopamine neuron dysfunction in transgenic Caenorhabditis elegans. J Biol Chem 281:334–340PubMedCrossRefGoogle Scholar
  114. Kwiatkowski TJ Jr et al (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323:1205–1208PubMedCrossRefGoogle Scholar
  115. Lagier-Tourenne C, Cleveland DW (2009) Rethinking ALS: the FUS about TDP-43. Cell 136:1001–1004PubMedPubMedCentralCrossRefGoogle Scholar
  116. Lai C, Lin X, Chandran J, Shim H, Yang WJ, Cai H (2007) The G59S mutation in p150(glued) causes dysfunction of dynactin in mice. J Neurosci 27:13982–13990PubMedPubMedCentralCrossRefGoogle Scholar
  117. Lakso M, Vartiainen S, Moilanen AM, Sirvio J, Thomas JH, Nass R, Blakely RD, Wong G (2003) Dopaminergic neuronal loss and motor deficits in Caenorhabditis elegans overexpressing human alpha-synuclein. J Neurochem 86:165–172PubMedCrossRefGoogle Scholar
  118. Langston JW, Irwin I (1986) MPTP: current concepts and controversies. Clin Neuropharmacol 9:485–507PubMedCrossRefGoogle Scholar
  119. 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
  120. Langston JW, Forno LS, Rebert CS, Irwin I (1984) Selective nigral toxicity after systemic administration of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyrine (MPTP) in the squirrel monkey. Brain Res 292:390–394PubMedCrossRefGoogle Scholar
  121. Langston JW, Forno LS, Tetrud J, Reeves AG, Kaplan JA, Karluk D (1999) Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure. Ann Neurol 46:598–605PubMedCrossRefGoogle Scholar
  122. Lapointe N, St-Hilaire M, Martinoli MG, Blanchet J, Gould P, Rouillard C, Cicchetti F (2004) Rotenone induces non-specific central nervous system and systemic toxicity. FASEB J 18:717–719PubMedCrossRefGoogle Scholar
  123. Laurie C, Reynolds A, Coskun O, Bowman E, Gendelman HE, Mosley RL (2007) CD4+ T cells from copolymer-1 immunized mice protect dopaminergic neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. J Neuroimmunol 183:60–68PubMedCrossRefGoogle Scholar
  124. 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
  125. LaVoie MJ, Ostaszewski BL, Weihofen A, Schlossmacher MG, Selkoe DJ (2005) Dopamine covalently modifies and functionally inactivates parkin. Nat Med 11:1214–1221PubMedCrossRefGoogle Scholar
  126. Lees AJ, Hardy J, Revesz T (2009) Parkinson’s disease. Lancet 373:2055–2066PubMedCrossRefGoogle Scholar
  127. Lehnardt S, Massillon L, Follett P, Jensen FE, Ratan R, Rosenberg PA, Volpe JJ, Vartanian T (2003) Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc Natl Acad Sci U S A 100:8514–8519PubMedPubMedCentralCrossRefGoogle Scholar
  128. Levy JR, Sumner CJ, Caviston JP, Tokito MK, Ranganathan S, Ligon LA, Wallace KE, LaMonte BH, Harmison GG, Puls I, Fischbeck KH, Holzbaur EL (2006) A motor neuron disease-associated mutation in p150Glued perturbs dynactin function and induces protein aggregation. J Cell Biol 172:733–745PubMedPubMedCentralCrossRefGoogle Scholar
  129. Liberatore GT, Jackson-Lewis V, Vukosavic S, Mandir AS, Vila M, McAuliffe WG, Dawson VL, Dawson TM, Przedborski S (1999) Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Nat Med 5:1403–1409PubMedCrossRefGoogle Scholar
  130. Limousin P, Krack P, Pollak P, Benazzouz A, Ardouin C, Hoffmann D, Benabid AL (1998) Electrical stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 339:1105–1111PubMedCrossRefGoogle Scholar
  131. Lin X, Parisiadou L, Gu XL, Wang L, Shim H, Sun L, Xie C, Long CX, Yang WJ, Ding J, Chen ZZ, Gallant PE, Tao-Cheng JH, Rudow G, Troncoso JC, Liu Z, Li Z, Cai H (2009) Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson’s-disease-related mutant alpha-synuclein. Neuron 64:807–827PubMedPubMedCentralCrossRefGoogle Scholar
  132. Lindeberg J, Usoskin D, Bengtsson H, Gustafsson A, Kylberg A, Soderstrom S, Ebendal T (2004) Transgenic expression of Cre recombinase from the tyrosine hydroxylase locus. Genesis 40:67–73PubMedCrossRefGoogle Scholar
  133. Ling Z, Gayle DA, Ma SY, Lipton JW, Tong CW, Hong JS, Carvey PM (2002) In utero bacterial endotoxin exposure causes loss of tyrosine hydroxylase neurons in the postnatal rat midbrain. Mov Disord 17:116–124PubMedCrossRefGoogle Scholar
  134. Ling ZD, Chang Q, Lipton JW, Tong CW, Landers TM, Carvey PM (2004) Combined toxicity of prenatal bacterial endotoxin exposure and postnatal 6-hydroxydopamine in the adult rat midbrain. Neuroscience 124:619–628PubMedCrossRefGoogle Scholar
  135. Liu B (2006) Modulation of microglial pro-inflammatory and neurotoxic activity for the treatment of Parkinson’s disease. AAPS J 8:E606–E621PubMedPubMedCentralCrossRefGoogle Scholar
  136. Liu Y, Roghani A, Edwards RH (1992) Gene transfer of a reserpine-sensitive mechanism of resistance to N-methyl-4-phenylpyridinium. Proc Natl Acad Sci U S A 89:9074–9078PubMedPubMedCentralCrossRefGoogle Scholar
  137. Liu B, Jiang JW, Wilson BC, Du L, Yang SN, Wang JY, Wu GC, Cao XD, Hong JS (2000) Systemic infusion of naloxone reduces degeneration of rat substantia nigral dopaminergic neurons induced by intranigral injection of lipopolysaccharide. J Pharmacol Exp Ther 295:125–132PubMedGoogle Scholar
  138. Liu Z, Wang X, Yu Y, Li X, Wang T, Jiang H, Ren Q, Jiao Y, Sawa A, Moran T, Ross CA, Montell C, Smith WW (2008) A Drosophila model for LRRK2-linked parkinsonism. Proc Natl Acad Sci U S A 105:2693–2698PubMedPubMedCentralCrossRefGoogle Scholar
  139. 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 U S A 99:10813–10818PubMedPubMedCentralCrossRefGoogle Scholar
  140. Lu X, Bing G, Hagg T (2000) Naloxone prevents microglia-induced degeneration of dopaminergic substantia nigra neurons in adult rats. Neuroscience 97:285–291PubMedCrossRefGoogle Scholar
  141. Lu XH, Fleming SM, Meurers B, Ackerson LC, Mortazavi F, Lo V, Hernandez D, Sulzer D, Jackson GR, Maidment NT, Chesselet MF, Yang XW (2009) Bacterial artificial chromosome transgenic mice expressing a truncated mutant parkin exhibit age-dependent hypokinetic motor deficits, dopaminergic neuron degeneration, and accumulation of proteinase K-resistant alpha-synuclein. J Neurosci 29:1962–1976PubMedPubMedCentralCrossRefGoogle Scholar
  142. Lucking CB, Durr A, Bonifati V, Vaughan J, De Michele G, Gasser T, Harhangi BS, Meco G, Denefle P, Wood NW, Agid Y, Brice A (2000) Association between early-onset Parkinson’s disease and mutations in the parkin gene. N Engl J Med 342:1560–1567PubMedCrossRefGoogle Scholar
  143. Luthman J, Fredriksson A, Sundstrom E, Jonsson G, Archer T (1989) Selective lesion of central dopamine or noradrenaline neuron systems in the neonatal rat: motor behavior and monoamine alterations at adult stage. Behav Brain Res 33:267–277PubMedCrossRefGoogle Scholar
  144. Lynch T, Farrer M, Hutton M, Hardy J (1997) Genetics of Parkinson’s disease. Science 278:1212–1213PubMedCrossRefGoogle Scholar
  145. 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
  146. Markey SP, Johannessen JN, Chiueh CC, Burns RS, Herkenham MA (1984) Intraneuronal generation of a pyridinium metabolite may cause drug-induced parkinsonism. Nature 311:464–467PubMedCrossRefGoogle Scholar
  147. Maroteaux L, Campanelli JT, Scheller RH (1988) Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci 8:2804–2815PubMedGoogle Scholar
  148. 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
  149. 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
  150. Mayer RA, Kindt MV, Heikkila RE (1986) Prevention of the nigrostriatal toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by inhibitors of 3,4-dihydroxyphenylethylamine transport. J Neurochem 47:1073–1079PubMedCrossRefGoogle Scholar
  151. McCormack AL, Thiruchelvam M, Manning-Bog AB, Thiffault C, Langston JW, Cory-Slechta DA, Di Monte DA (2002) Environmental risk factors and Parkinson’s disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat. Neurobiol Dis 10:119–127PubMedCrossRefGoogle Scholar
  152. McCoy MK, Martinez TN, Ruhn KA, Szymkowski DE, Smith CG, Botterman BR, Tansey KE, Tansey MG (2006) Blocking soluble tumor necrosis factor signaling with dominant-negative tumor necrosis factor inhibitor attenuates loss of dopaminergic neurons in models of Parkinson’s disease. J Neurosci 26: 9365–9375PubMedPubMedCentralCrossRefGoogle Scholar
  153. McGeer PL, Itagaki S, Boyes BE, McGeer EG (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 38:1285–1291PubMedCrossRefGoogle Scholar
  154. 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
  155. Melrose H, Lincoln S, Tyndall G, Dickson D, Farrer M (2006) Anatomical localization of leucine-rich repeat kinase 2 in mouse brain. Neuroscience 139:791–794PubMedCrossRefGoogle Scholar
  156. Menzies FM, Yenisetti SC, Min KT (2005) Roles of Drosophila DJ-1 in survival of dopaminergic neurons and oxidative stress. Curr Biol 15:1578–1582PubMedCrossRefGoogle Scholar
  157. Meulener M, Whitworth AJ, Armstrong-Gold CE, Rizzu P, Heutink P, Wes PD, Pallanck LJ, Bonini NM (2005) Drosophila DJ-1 mutants are selectively sensitive to environmental toxins associated with Parkinson’s disease. Curr Biol 15:1572–1577PubMedCrossRefGoogle Scholar
  158. Mitchell JD (1987) Heavy metals and trace elements in amyotrophic lateral sclerosis. Neurol Clin 5:43–60PubMedGoogle Scholar
  159. Mizuno Y, Hattori N, Mori H, Suzuki T, Tanaka K (2001) Parkin and Parkinson’s disease. Curr Opin Neurol 14:477–482PubMedCrossRefGoogle Scholar
  160. Moratalla R, Quinn B, DeLanney LE, Irwin I, Langston JW, Graybiel AM (1992) Differential vulnerability of primate caudate-putamen and striosome-matrix dopamine systems to the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proc Natl Acad Sci U S A 89:3859–3863PubMedPubMedCentralCrossRefGoogle Scholar
  161. Nakagawa S, Yoshida S, Suematsu C, Shimizu E, Hirohata T, Kumamoto T, Yase Y, Kawai K, Iwata S (1977) The calcium-magnesium-deficient rat: a study on the distribution of calcium in the spinal cord using the electron probe microanalyser. Experientia 33: 1225–1226PubMedCrossRefGoogle Scholar
  162. Natale G, Kastsiushenka O, Fulceri F, Ruggieri S, Paparelli A, Fornai F (2010) MPTP-induced parkinsonism extends to a subclass of TH-positive neurons in the gut. Brain Res 1355:195–206PubMedCrossRefGoogle Scholar
  163. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133PubMedCrossRefGoogle Scholar
  164. Nicklas WJ, Vyas I, Heikkila RE (1985) 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 36:2503–2508PubMedCrossRefGoogle Scholar
  165. Nishimura AL, Mitne-Neto M, Silva HC, Richieri-Costa A, Middleton S, Cascio D, Kok F, Oliveira JR, Gillingwater T, Webb J, Skehel P, Zatz M (2004) A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet 75:822–831PubMedPubMedCentralCrossRefGoogle Scholar
  166. Nissl F (1892) Uber die veraenderungen der ganglienzellen am facialiskern des kaninchens nach ausreissung der nerve. Allg Z Psychiatr 48:197–198Google Scholar
  167. Paisan-Ruiz C et al (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron 44:595–600PubMedCrossRefGoogle Scholar
  168. Pamphlett R, Kum-Jew S (2001) Mercury vapor uptake into the nervous system of developing mice. Neurotoxicol Teratol 23:191–196PubMedCrossRefGoogle Scholar
  169. Pamphlett R, Slater M, Thomas S (1998) Oxidative damage to nucleic acids in motor neurons containing mercury. J Neurol Sci 159:121–126PubMedCrossRefGoogle Scholar
  170. Park J, Lee SB, Lee S, Kim Y, Song S, Kim S, Bae E, Kim J, Shong M, Kim JM, Chung J (2006) Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 441:1157–1161PubMedCrossRefGoogle Scholar
  171. Pendleton RG, Parvez F, Sayed M, Hillman R (2002) Effects of pharmacological agents upon a transgenic model of Parkinson’s disease in Drosophila melanogaster. J Pharmacol Exp Ther 300:91–96PubMedCrossRefGoogle Scholar
  172. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047PubMedCrossRefGoogle Scholar
  173. Pramatarova A, Laganiere J, Roussel J, Brisebois K, Rouleau GA (2001) Neuron-specific expression of mutant superoxide dismutase 1 in transgenic mice does not lead to motor impairment. J Neurosci 21: 3369–3374PubMedGoogle Scholar
  174. Przedborski S, Levivier M, Jiang H, Ferreira M, Jackson-Lewis V, Donaldson D, Togasaki DM (1995) Dose-dependent lesions of the dopaminergic nigrostriatal pathway induced by intrastriatal injection of 6-hydroxydopamine. Neuroscience 67:631–647PubMedCrossRefGoogle Scholar
  175. Przedborski S, Jackson-Lewis V, Naini AB, Jakowec M, Petzinger G, Miller R, Akram M (2001) The parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): a technical review of its utility and safety. J Neurochem 76:1265–1274PubMedCrossRefGoogle Scholar
  176. Puls I, Jonnakuty C, LaMonte BH, Holzbaur EL, Tokito M, Mann E, Floeter MK, Bidus K, Drayna D, Oh SJ, Brown RH Jr, Ludlow CL, Fischbeck KH (2003) Mutant dynactin in motor neuron disease. Nat Genet 33:455–456PubMedCrossRefGoogle Scholar
  177. Ramsay RR, Singer TP (1986) 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 261:7585–7587PubMedGoogle Scholar
  178. Rathke-Hartlieb S, Schmidt VC, Jockusch H, Schmitt-John T, Bartsch JW (1999) Spatiotemporal progression of neurodegeneration and glia activation in the wobbler neuropathy of the mouse. Neuroreport 10:3411–3416PubMedCrossRefGoogle Scholar
  179. Reynolds AD, Banerjee R, Liu J, Gendelman HE, Mosley RL (2007) Neuroprotective activities of CD4+CD25+ regulatory T cells in an animal model of Parkinson’s disease. J Leukoc Biol 82:1083–1094PubMedCrossRefGoogle Scholar
  180. Reynolds AD, Glanzer JG, Kadiu I, Ricardo-Dukelow M, Chaudhuri A, Ciborowski P, Cerny R, Gelman B, Thomas MP, Mosley RL, Gendelman HE (2008) Nitrated alpha-synuclein-activated microglial profiling for Parkinson’s disease. J Neurochem 104:1504–1525PubMedCrossRefGoogle Scholar
  181. Reynolds AD, Stone DK, Mosley RL, Gendelman HE (2009a) Nitrated {alpha}-synuclein-induced alterations in microglial immunity are regulated by CD4+ T cell subsets. J Immunol 182:4137–4149PubMedPubMedCentralCrossRefGoogle Scholar
  182. Reynolds AD, Stone DK, Mosley RL, Gendelman HE (2009b) Proteomic studies of nitrated alpha-synuclein microglia regulation by CD4+CD25+ T cells. J Proteome Res 8:3497–3511PubMedPubMedCentralCrossRefGoogle Scholar
  183. Reynolds AD, Stone DK, Hutter JA, Benner EJ, Mosley RL, Gendelman HE (2010) Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson’s disease. J Immunol 184:2261–2271PubMedPubMedCentralCrossRefGoogle Scholar
  184. 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
  185. Romero R, Manogue KR, Mitchell MD, Wu YK, Oyarzun E, Hobbins JC, Cerami A (1989) Infection and labor. IV. Cachectin-tumor necrosis factor in the amniotic fluid of women with intraamniotic infection and preterm labor. Am J Obstet Gynecol 161:336–341PubMedCrossRefGoogle Scholar
  186. Saha S, Guillily MD, Ferree A, Lanceta J, Chan D, Ghosh J, Hsu CH, Segal L, Raghavan K, Matsumoto K, Hisamoto N, Kuwahara T, Iwatsubo T, Moore L, Goldstein L, Cookson M, Wolozin B (2009) LRRK2 modulates vulnerability to mitochondrial dysfunction in Caenorhabditis elegans. J Neurosci 29:9210–9218PubMedPubMedCentralCrossRefGoogle Scholar
  187. Sang TK, Chang HY, Lawless GM, Ratnaparkhi A, Mee L, Ackerson LC, Maidment NT, Krantz DE, Jackson GR (2007) A Drosophila model of mutant human parkin-induced toxicity demonstrates selective loss of dopaminergic neurons and dependence on cellular dopamine. J Neurosci 27:981–992PubMedCrossRefGoogle Scholar
  188. Sauer H, Oertel WH (1994) Progressive degeneration of nigrostriatal dopamine neurons following intrastriatal terminal lesions with 6-hydroxydopamine: a combined retrograde tracing and immunocytochemical study in the rat. Neuroscience 59:401–415PubMedCrossRefGoogle Scholar
  189. Sawada H, Kohno R, Kihara T, Izumi Y, Sakka N, Ibi M, Nakanishi M, Nakamizo T, Yamakawa K, Shibasaki H, Yamamoto N, Akaike A, Inden M, Kitamura Y, Taniguchi T, Shimohama S (2004) Proteasome mediates dopaminergic neuronal degeneration, and its inhibition causes alpha-synuclein inclusions. J Biol Chem 279:10710–10719PubMedCrossRefGoogle Scholar
  190. Schmalbruch H, Jensen HJ, Bjaerg M, Kamieniecka Z, Kurland L (1991) A new mouse mutant with progressive motor neuronopathy. J Neuropathol Exp Neurol 50:192–204PubMedCrossRefGoogle Scholar
  191. Schober A (2004) Classic toxin-induced animal models of Parkinson’s disease: 6-OHDA and MPTP. Cell Tissue Res 318:215–224PubMedCrossRefGoogle Scholar
  192. 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
  193. Shibata N (2001) Transgenic mouse model for familial amyotrophic lateral sclerosis with superoxide dismutase-1 mutation. Neuropathology 21:82–92PubMedCrossRefGoogle Scholar
  194. Shimizu K, Ohtaki K, Matsubara K, Aoyama K, Uezono T, Saito O, Suno M, Ogawa K, Hayase N, Kimura K, Shiono H (2001) Carrier-mediated processes in blood–brain barrier penetration and neural uptake of paraquat. Brain Res 906:135–142PubMedCrossRefGoogle Scholar
  195. Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, Minoshima S, Shimizu N, Iwai K, Chiba T, Tanaka K, Suzuki T (2000) Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet 25:302–305PubMedCrossRefGoogle Scholar
  196. Silvestri L, Caputo V, Bellacchio E, Atorino L, Dallapiccola B, Valente EM, Casari G (2005) Mitochondrial import and enzymatic activity of PINK1 mutants associated to recessive parkinsonism. Hum Mol Genet 14:3477–3492PubMedCrossRefGoogle Scholar
  197. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840PubMedCrossRefGoogle Scholar
  198. Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M (1998) Alpha-synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proc Natl Acad Sci U S A 95:6469–6473PubMedPubMedCentralCrossRefGoogle Scholar
  199. Sriram SR, Li X, Ko HS, Chung KK, Wong E, Lim KL, Dawson VL, Dawson TM (2005) Familial-associated mutations differentially disrupt the solubility, localization, binding and ubiquitination properties of parkin. Hum Mol Genet 14:2571–2586PubMedCrossRefGoogle Scholar
  200. Subramaniam JR, Lyons WE, Liu J, Bartnikas TB, Rothstein J, Price DL, Cleveland DW, Gitlin JD, Wong PC (2002) Mutant SOD1 causes motor neuron disease independent of copper chaperone-mediated copper loading. Nat Neurosci 5:301–307PubMedCrossRefGoogle Scholar
  201. Takahashi K, Taira T, Niki T, Seino C, Iguchi-Ariga SM, Ariga H (2001) DJ-1 positively regulates the androgen receptor by impairing the binding of PIASx alpha to the receptor. J Biol Chem 276:37556–37563PubMedCrossRefGoogle Scholar
  202. Talpade DJ, Greene JG, Higgins DS Jr, Greenamyre JT (2000) In vivo labeling of mitochondrial complex I (NADH:ubiquinone oxidoreductase) in rat brain using [(3)H]dihydrorotenone. J Neurochem 75:2611–2621PubMedCrossRefGoogle Scholar
  203. Terzioglu M, Galter D (2008) Parkinson’s disease: genetic versus toxin-induced rodent models. FEBS J 275: 1384–1391PubMedCrossRefGoogle Scholar
  204. Teuling E, van Dis V, Wulf PS, Haasdijk ED, Akhmanova A, Hoogenraad CC, Jaarsma D (2008) A novel mouse model with impaired dynein/dynactin function develops amyotrophic lateral sclerosis (ALS)-like features in motor neurons and improves lifespan in SOD1-ALS mice. Hum Mol Genet 17:2849–2862PubMedCrossRefGoogle Scholar
  205. Theodore S, Cao S, McLean PJ, Standaert DG (2008) Targeted overexpression of human alpha-synuclein triggers microglial activation and an adaptive immune response in a mouse model of Parkinson disease. J Neuropathol Exp Neurol 67:1149–1158PubMedPubMedCentralCrossRefGoogle Scholar
  206. Thiruchelvam M, Richfield EK, Baggs RB, Tank AW, Cory-Slechta DA (2000a) The nigrostriatal dopaminergic system as a preferential target of repeated exposures to combined paraquat and maneb: implications for Parkinson’s disease. J Neurosci 20:9207–9214PubMedGoogle Scholar
  207. Thiruchelvam M, Brockel BJ, Richfield EK, Baggs RB, Cory-Slechta DA (2000b) Potentiated and preferential effects of combined paraquat and maneb on nigrostriatal dopamine systems: environmental risk factors for Parkinson’s disease? Brain Res 873:225–234PubMedCrossRefGoogle Scholar
  208. Thiruchelvam MJ, Powers JM, Cory-Slechta DA, Richfield EK (2004) Risk factors for dopaminergic neuron loss in human alpha-synuclein transgenic mice. Eur J Neurosci 19:845–854PubMedCrossRefGoogle Scholar
  209. Troncoso JC, Price DL, Griffin JW, Parhad IM (1982) Neurofibrillary axonal pathology in aluminum intoxication. Ann Neurol 12:278–283PubMedCrossRefGoogle Scholar
  210. Tudor EL, Galtrey CM, Perkinton MS, Lau KF, De Vos KJ, Mitchell JC, Ackerley S, Hortobagyi T, Vamos E, Leigh PN, Klasen C, McLoughlin DM, Shaw CE, Miller CC (2010) Amyotrophic lateral sclerosis mutant vesicle-associated membrane protein-associated protein-B transgenic mice develop TAR-DNA-binding protein-43 pathology. Neuroscience 167:774–785PubMedCrossRefGoogle Scholar
  211. Turiault M, Parnaudeau S, Milet A, Parlato R, Rouzeau JD, Lazar M, Tronche F (2007) Analysis of dopamine transporter gene expression pattern—generation of DAT-iCre transgenic mice. FEBS J 274:3568–3577PubMedCrossRefGoogle Scholar
  212. Ungerstedt U (1968) 6-Hydroxy-dopamine induced degeneration of central monoamine neurons. Eur J Pharmacol 5:107–110PubMedCrossRefGoogle Scholar
  213. Ungerstedt U (1971) Postsynaptic supersensitivity after 6-hydroxy-dopamine induced degeneration of the nigro-striatal dopamine system. Acta Physiol Scand Suppl 367:69–93PubMedCrossRefGoogle Scholar
  214. Ungerstedt U, Arbuthnott GW (1970) Quantitative recording of rotational behavior in rats after 6-hydroxy-dopamine lesions of the nigrostriatal dopamine system. Brain Res 24:485–493PubMedCrossRefGoogle Scholar
  215. Valente EM et al (2004) Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304:1158–1160PubMedCrossRefGoogle Scholar
  216. Van Den Bosch L, Tilkin P, Lemmens G, Robberecht W (2002) Minocycline delays disease onset and mortality in a transgenic model of ALS. Neuroreport 13: 1067–1070CrossRefGoogle Scholar
  217. Vance C et al (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323:1208–1211PubMedPubMedCentralCrossRefGoogle Scholar
  218. von Coelln R, Dawson VL, Dawson TM (2004) Parkin-associated Parkinson’s disease. Cell Tissue Res 318:175–184CrossRefGoogle Scholar
  219. Wang C, Lu R, Ouyang X, Ho MW, Chia W, Yu F, Lim KL (2007) Drosophila overexpressing parkin R275W mutant exhibits dopaminergic neuron degeneration and mitochondrial abnormalities. J Neurosci 27:8563–8570PubMedCrossRefGoogle Scholar
  220. Wegorzewska I, Bell S, Cairns NJ, Miller TM, Baloh RH (2009) TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci U S A 106:18809–18814PubMedPubMedCentralCrossRefGoogle Scholar
  221. 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 U S A 102:16842–16847PubMedPubMedCentralCrossRefGoogle Scholar
  222. Widdowson PS, Farnworth MJ, Simpson MG, Lock EA (1996a) Influence of age on the passage of paraquat through the blood-brain barrier in rats: a distribution and pathological examination. Hum Exp Toxicol 15: 231–236PubMedCrossRefGoogle Scholar
  223. Widdowson PS, Farnworth MJ, Upton R, Simpson MG (1996b) No changes in behaviour, nigro-striatal system neurochemistry or neuronal cell death following toxic multiple oral paraquat administration to rats. Hum Exp Toxicol 15:583–591PubMedCrossRefGoogle Scholar
  224. Wils H, Kleinberger G, Janssens J, Pereson S, Joris G, Cuijt I, Smits V, Ceuterick-de Groote C, Van Broeckhoven C, Kumar-Singh S (2010) TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci U S A 107: 3858–3863PubMedPubMedCentralCrossRefGoogle Scholar
  225. Yase Y (1987) The pathogenetic role of metals in motor neuron disease—the participation of aluminum. In: Cosi V, Kato A, Parlette W, Pinelli P, Poloni M (eds) Amyotrophic lateral sclerosis: therapeutic, psychological and research aspects. Plenum, New York, pp 89–96CrossRefGoogle Scholar
  226. 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
  227. Zhou W, Zhu M, Wilson MA, Petsko GA, Fink AL (2006) The oxidation state of DJ-1 regulates its chaperone activity toward alpha-synuclein. J Mol Biol 356: 1036–1048PubMedCrossRefGoogle Scholar
  228. Zhu S, Stavrovskaya IG, Drozda M, Kim BY, Ona V, Li M, Sarang S, Liu AS, Hartley DM, Wu DC, Gullans S, Ferrante RJ, Przedborski S, Kristal BS, Friedlander RM (2002) Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature 417:74–78PubMedCrossRefGoogle Scholar
  229. Zhu X, Siedlak SL, Smith MA, Perry G, Chen SG (2006) LRRK2 protein is a component of Lewy bodies. Ann Neurol 60:617–618, author reply 618–619PubMedCrossRefGoogle Scholar
  230. Zhuang X, Masson J, Gingrich JA, Rayport S, Hen R (2005) Targeted gene expression in dopamine and serotonin neurons of the mouse brain. J Neurosci Methods 143:27–32PubMedCrossRefGoogle Scholar
  231. Zimprich A et al (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44:601–607PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Max V. Kuenstling
    • 1
  • Adam M. Szlachetka
    • 1
  • R. Lee Mosley
    • 1
  1. 1.Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative DisordersUniversity of Nebraska Medical CenterOmahaUSA

Personalised recommendations