Genes & Genomics

, Volume 36, Issue 4, pp 399–413 | Cite as

Animal models of amyotrophic lateral sclerosis and Huntington’s disease

  • Abu M. T. Islam
  • Jina Kwak
  • Yoo Jung Jung
  • Yun Kee
Review

Abstract

Amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD) are debilitating neurodegenerative conditions for which there is no effective cure. Genetic determinants of both diseases have been identified, providing insight into neuropathological mechanisms and opportunities for therapeutic intervention. Aggregation of mutant proteins is the most prominent phenotype of these neurodegenerative diseases as is the case in Alzheimer’s disease and Parkinson’s disease. Here we review transgenic animal models of ALS and HD in mouse, zebrafish, C. elegans, and Drosophila that have been developed to study different aspects of disease progression. We also cover some large mammal transgenic models that have been recently developed. To effectively tackle these conditions will likely require effective use of several of these animal models, as each offers distinct advantages and insights into disease pathology.

Keywords

Neurodegenerative diseases Amyotrophic lateral sclerosis Huntington’s disease Animal models Disease pathology 

References

  1. Ash PE, Zhang YJ, Roberts CM, Saldi T, Hutter H, Buratti E, Petrucelli L, Link CD (2010) Neurotoxic effects of TDP-43 overexpression in C. elegans. Hum Mol Genet 19:3206–3218PubMedCentralPubMedCrossRefGoogle Scholar
  2. Bosco DA, Lemay N, Ko HK, Zhou H, Burke C, Kwiatkowski TJ Jr, Sapp P, McKenna-Yasek D, Brown RH Jr, Hayward LJ (2010) Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules. Hum Mol Genet 19:4160–4175PubMedCentralPubMedCrossRefGoogle Scholar
  3. Bruijn LI, Becher MW, Lee MK, Anderson KL, Jenkins NA, Copeland NG, Sisodia SS, Rothstein JD, Borchelt DR, Price DL et al (1997) ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 18:327–338PubMedCrossRefGoogle Scholar
  4. Brustovetsky N, LaFrance R, Purl KJ, Brustovetsky T, Keene CD, Low WC, Dubinsky JM (2005) Age-dependent changes in the calcium sensitivity of striatal mitochondria in mouse models of Huntington’s disease. J Neurochem 93:1361–1370PubMedCrossRefGoogle Scholar
  5. Cai H, Lin X, Xie C, Laird FM, Lai C, Wen H, Chiang HC, Shim H, Farah MH, Hoke A et al (2005) Loss of ALS2 function is insufficient to trigger motor neuron degeneration in knock-out mice but predisposes neurons to oxidative stress. J Neurosci 25:7567–7574PubMedCentralPubMedCrossRefGoogle Scholar
  6. Caine ED, Hunt RD, Weingartner H, Ebert MH (1978) Huntington’s dementia. Clinical and neuropsychological features. Arch Gen Psychiatry 35:377–384PubMedCrossRefGoogle Scholar
  7. Cannon A, Yang B, Knight J, Farnham IM, Zhang Y, Wuertzer CA, D’Alton S, Lin WL, Castanedes-Casey M, Rousseau L et al (2012) Neuronal sensitivity to TDP-43 overexpression is dependent on timing of induction. Acta Neuropathol 123:807–823PubMedCentralPubMedCrossRefGoogle Scholar
  8. Cheng PH, Li CL, Her LS, Chang YF, Chan AWS, Chen CM, Yang SH (2013) Significantly differential diffusion of neuropathological aggregates in the brain of transgenic mice carrying N-terminal mutant huntingtin fused with green fluorescent protein. Brain Struct Funct 218:283–294PubMedCrossRefGoogle Scholar
  9. Chevalier-Larsen ES, Wallace KE, Pennise CR, Holzbaur EL (2008) Lysosomal proliferation and distal degeneration in motor neurons expressing the G59S mutation in the p150Glued subunit of dynactin. Hum Mol Genet 17:1946–1955PubMedCentralPubMedCrossRefGoogle Scholar
  10. Chiang PM, Ling J, Jeong YH, Price DL, Aja SM, Wong PC (2010) Deletion of TDP-43 down-regulates Tbc1d1, a gene linked to obesity, and alters body fat metabolism. Proc Natl Acad Sci USA 107:16320–16324PubMedCentralPubMedCrossRefGoogle Scholar
  11. Chieppa MN, Perota A, Corona C, Grindatto A, Lagutina I, Vallino Costassa E, Lazzari G, Colleoni S, Duchi R, Lucchini F et al (2013) Modeling Amyotrophic Lateral Sclerosis in hSOD1 Transgenic Swine. Neurodegener Dis. doi:10.1159/000353472
  12. Da Costa MM, Allen CE, Higginbottom A, Ramesh T, Shaw PJ, McDermott CJ (2014) A new zebrafish model produced by TILLING of SOD1-related amyotrophic lateral sclerosis replicates key features of the disease and represents a tool for in vivo therapeutic screening. Dis Model Mech 7:73–81PubMedCentralPubMedCrossRefGoogle Scholar
  13. Deng HX, Hentati A, Tainer JA, Iqbal Z, Cayabyab A, Hung WY, Getzoff ED, Hu P, Herzfeldt B, Roos RP et al (1993) Amyotrophic lateral sclerosis and structural defects in Cu, Zn superoxide dismutase. Science 261:1047–1051PubMedCrossRefGoogle Scholar
  14. Devon RS, Orban PC, Gerrow K, Barbieri MA, Schwab C, Cao LP, Helm JR, Bissada N, Cruz-Aguado R, Davidson TL et al (2006) Als2-deficient mice exhibit disturbances in endosome trafficking associated with motor behavioral abnormalities. Proc Natl Acad Sci USA 103:9595–9600PubMedCentralPubMedCrossRefGoogle Scholar
  15. Elshafey A, Lanyon WG, Connor JM (1994) Identification of a new missense point mutation in exon 4 of the Cu/Zn superoxide dismutase (SOD-1) gene in a family with amyotrophic lateral sclerosis. Hum Mol Genet 3:363–364PubMedCrossRefGoogle Scholar
  16. Faber PW, Alter JR, MacDonald ME, Hart AC (1999) Polyglutamine-mediated dysfunction and apoptotic death of a Caenorhabditis elegans sensory neuron. Proc Natl Acad Sci USA 96:179–184PubMedCentralPubMedCrossRefGoogle Scholar
  17. Faber PW, Voisine C, King DC, Bates EA, Hart AC (2002) Glutamine/proline-rich PQE-1 proteins protect Caenorhabditis elegans neurons from huntingtin polyglutamine neurotoxicity. Proc Natl Acad Sci USA 99:17131–17136PubMedCentralPubMedCrossRefGoogle Scholar
  18. Feiguin F, Godena VK, Romano G, D’Ambrogio A, Klima R, Baralle FE (2009) Depletion of TDP-43 affects Drosophila motoneurons terminal synapsis and locomotive behavior. FEBS Lett 583:1586–1592PubMedCrossRefGoogle Scholar
  19. Ferre S, O’Connor WT, Fuxe K, Ungerstedt U (1993) The striopallidal neuron: a main locus for adenosine-dopamine interactions in the brain. J Neurosci 13:5402–5406PubMedGoogle Scholar
  20. Gray M, Shirasaki DI, Cepeda C, Andre VM, Wilburn B, Lu XH, Tao J, Yamazaki I, Li SH, Sun YE et al (2008) Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice. J Neurosci 28:6182–6195PubMedCentralPubMedCrossRefGoogle Scholar
  21. Graybiel AM (1990) Neurotransmitters and neuromodulators in the basal ganglia. Trends Neurosci 13:244–254PubMedCrossRefGoogle Scholar
  22. Gros-Louis F, Kriz J, Kabashi E, McDearmid J, Millecamps S, Urushitani M, Lin L, Dion P, Zhu Q, Drapeau P et al (2008) Als2 mRNA splicing variants detected in KO mice rescue severe motor dysfunction phenotype in Als2 knock-down zebrafish. Hum Mol Genet 17:2691–2702PubMedCrossRefGoogle Scholar
  23. 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
  24. Hadano S, Benn SC, Kakuta S, Otomo A, Sudo K, Kunita R, Suzuki-Utsunomiya K, Mizumura H, Shefner JM, Cox GA et al (2006) Mice deficient in the Rab5 guanine nucleotide exchange factor ALS2/alsin exhibit age-dependent neurological deficits and altered endosome trafficking. Hum Mol Genet 15:233–250Google Scholar
  25. Harte PJ, Kankel DR (1982) Genetic analysis of mutations at the Glued locus and interacting loci in Drosophila melanogaster. Genetics 101:477–501PubMedCentralPubMedGoogle Scholar
  26. Haverkamp LJ, Appel V, Appel SH (1995) Natural history of amyotrophic lateral sclerosis in a database population. Validation of a scoring system and a model for survival prediction. Brain 118(Pt 3):707–719PubMedCrossRefGoogle Scholar
  27. Heinsen H, Strik M, Bauer M, Luther K, Ulmar G, Gangnus D, Jungkunz G, Eisenmenger W, Gotz M (1994) Cortical and striatal neurone number in Huntington’s disease. Acta Neuropathol 88:320–333PubMedCrossRefGoogle Scholar
  28. Heng MY, Duong DK, Albin RL, Tallaksen-Greene SJ, Hunter JM, Lesort MJ, Osmand A, Paulson HL, Detloff PJ (2010) Early autophagic response in a novel knock-in model of Huntington disease. Hum Mol Genet 19:3702–3720Google Scholar
  29. Heng MY, Tallaksen-Greene SJ, Detloff PJ, Albin RL (2007) Longitudinal evaluation of the Hdh(CAG)150 knock-in murine model of Huntington’s disease. J Neurosci 27:8989–8998PubMedCrossRefGoogle Scholar
  30. Hodgson JG, Agopyan N, Gutekunst CA, Leavitt BR, LePiane F, Singaraja R, Smith DJ, Bissada N, McCutcheon K, Nasir J et al (1999) A YAC mouse model for Huntington’s disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron 23:181–192PubMedCrossRefGoogle Scholar
  31. Holzbaur EL (2004) Motor neurons rely on motor proteins. Trends Cell Biol 14:233–240PubMedCrossRefGoogle Scholar
  32. Igaz LM, Kwong LK, Lee EB, Chen-Plotkin A, Swanson E, Unger T, Malunda J, Xu Y, Winton MJ, Trojanowski JQ et al (2011) Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice. J Clin Invest 121:726–738PubMedCentralPubMedCrossRefGoogle Scholar
  33. Jackson GR, Salecker I, Dong X, Yao X, Arnheim N, Faber PW, MacDonald ME, Zipursky SL (1998) Polyglutamine-expanded human huntingtin transgenes induce degeneration of Drosophila photoreceptor neurons. Neuron 21:633–642PubMedCrossRefGoogle Scholar
  34. Jacobsen JC, Bawden CS, Rudiger SR, McLaughlan CJ, Reid SJ, Waldvogel HJ, MacDonald ME, Gusella JF, Walker SK, Kelly JM et al (2010) An ovine transgenic Huntington’s disease model. Hum Mol Genet 19:1873–1882PubMedCentralPubMedCrossRefGoogle Scholar
  35. Jarabek BR, Yasuda RP, Wolfe BB (2004) Regulation of proteins affecting NMDA receptor-induced excitotoxicity in a Huntington’s mouse model. Brain 127:505–516PubMedCrossRefGoogle Scholar
  36. Jonsson PA, Graffmo KS, Brannstrom T, Nilsson P, Andersen PM, Marklund SL (2006) Motor neuron disease in mice expressing the wild type-like D90A mutant superoxide dismutase-1. J Neuropathol Exp Neurol 65:1126–1136PubMedCrossRefGoogle Scholar
  37. Kabashi E, Valdmanis PN, Dion P, Spiegelman D, McConkey BJ, Vande Velde C, Bouchard JP, Lacomblez L, Pochigaeva K, Salachas F et al (2008) TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 40:572–574PubMedCrossRefGoogle Scholar
  38. Kabashi E, Lin L, Tradewell ML, Dion PA, Bercier V, Bourgouin P, Rochefort D, Bel Hadj S, Durham HD, Vande Velde C et al (2010) Gain and loss of function of ALS-related mutations of TARDBP (TDP-43) cause motor deficits in vivo. Hum Mol Genet 19:671–683PubMedCrossRefGoogle Scholar
  39. Kaltenbach LS, Romero E, Becklin RR, Chettier R, Bell R, Phansalkar A, Strand A, Torcassi C, Savage J, Hurlburt A et al (2007) Huntingtin interacting proteins are genetic modifiers of neurodegeneration. PLoS Genet 3:e82PubMedCentralPubMedCrossRefGoogle Scholar
  40. Karlovich CA, John RM, Ramirez L, Stainier DY, Myers RM (1998) Characterization of the Huntington’s disease (HD) gene homologue in the zebrafish Danio rerio. Gene 217:117–125PubMedCrossRefGoogle Scholar
  41. Kraemer BC, Schuck T, Wheeler JM, Robinson LC, Trojanowski JQ, Lee VM, Schellenberg GD (2010) Loss of murine TDP-43 disrupts motor function and plays an essential role in embryogenesis. Acta Neuropathol 119:409–419PubMedCentralPubMedCrossRefGoogle Scholar
  42. Kremer B, Goldberg P, Andrew SE, Theilmann J, Telenius H, Zeisler J, Squitieri F, Lin B, Bassett A, Almqvist E et al (1994) A worldwide study of the Huntington’s disease mutation. The sensitivity and specificity of measuring CAG repeats. N Engl J Med 330:1401–1406PubMedCrossRefGoogle Scholar
  43. Laforet GA, Sapp E, Chase K, McIntyre C, Boyce FM, Campbell M, Cadigan BA, Warzecki L, Tagle DA, Reddy PH et al (2001) Changes in cortical and striatal neurons predict behavioral and electrophysiological abnormalities in a transgenic murine model of Huntington’s disease. J Neurosci 21:9112–9123PubMedGoogle Scholar
  44. 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 27:13982–13990PubMedCentralPubMedCrossRefGoogle Scholar
  45. Laird FM, Farah MH, Ackerley S, Hoke A, Maragakis N, Rothstein JD, Griffin J, Price DL, Martin LJ, Wong PC (2008) Motor neuron disease occurring in a mutant dynactin mouse model is characterized by defects in vesicular trafficking. J Neurosci 28:1997–2005PubMedCrossRefGoogle Scholar
  46. LaMonte BH, Wallace KE, Holloway BA, Shelly SS, Ascano J, Tokito M, Van Winkle T, Howland DS, Holzbaur EL (2002) Disruption of dynein/dynactin inhibits axonal transport in motor neurons causing late-onset progressive degeneration. Neuron 34:715–727PubMedCrossRefGoogle Scholar
  47. Lanson NA Jr, Maltare A, King H, Smith R, Kim JH, Taylor JP, Lloyd TE, Pandey UB (2011) A Drosophila model of FUS-related neurodegeneration reveals genetic interaction between FUS and TDP-43. Hum Mol Genet 20:2510–2523PubMedCentralPubMedCrossRefGoogle Scholar
  48. Lee WC, Yoshihara M, Littleton JT (2004) Cytoplasmic aggregates trap polyglutamine-containing proteins and block axonal transport in a Drosophila model of Huntington’s disease. Proc Natl Acad Sci USA 101:3224–3229PubMedCentralPubMedCrossRefGoogle Scholar
  49. Lemmens R, Van Hoecke A, Hersmus N, Geelen V, D’Hollander I, Thijs V, Van Den Bosch L, Carmeliet P, Robberecht W (2007) Overexpression of mutant superoxide dismutase 1 causes a motor axonopathy in the zebrafish. Hum Mol Genet 16:2359–2365PubMedCrossRefGoogle Scholar
  50. Li JY, Plomann M, Brundin P (2003) Huntington’s disease: a synaptopathy? Trends Mol Med 9:414–420PubMedCrossRefGoogle Scholar
  51. Li JY, Popovic N, Brundin P (2005) The use of the R6 transgenic mouse models of Huntington’s disease in attempts to develop novel therapeutic strategies. NeuroRx 2:447–464PubMedCentralPubMedCrossRefGoogle Scholar
  52. Lin CH, Tallaksen-Greene S, Chien WM, Cearley JA, Jackson WS, Crouse AB, Ren S, Li XJ, Albin RL, Detloff PJ (2001) Neurological abnormalities in a knock-in mouse model of Huntington’s disease. Hum Mol Genet 10:137–144PubMedCrossRefGoogle Scholar
  53. Lin MJ, Cheng CW, Shen CK (2011) Neuronal function and dysfunction of Drosophila dTDP. PLoS ONE 6:e20371PubMedCentralPubMedCrossRefGoogle Scholar
  54. Lu Y, Ferris J, Gao FB (2009) Frontotemporal dementia and amyotrophic lateral sclerosis-associated disease protein TDP-43 promotes dendritic branching. Mol Brain 2:30PubMedCentralPubMedCrossRefGoogle Scholar
  55. Lumsden AL, Henshall TL, Dayan S, Lardelli MT, Richards RI (2007) Huntingtin-deficient zebrafish exhibit defects in iron utilization and development. Hum Mol Genet 16:1905–1920PubMedCrossRefGoogle Scholar
  56. Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, Lawton M, Trottier Y, Lehrach H, Davies SW et al (1996) Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87:493–506PubMedCrossRefGoogle Scholar
  57. Martin M, Iyadurai SJ, Gassman A, Gindhart JG Jr, Hays TS, Saxton WM (1999) Cytoplasmic dynein, the dynactin complex, and kinesin are interdependent and essential for fast axonal transport. Mol Biol Cell 10:3717–3728PubMedCentralPubMedCrossRefGoogle Scholar
  58. Menalled LB, Sison JD, Dragatsis I, Zeitlin S, Chesselet MF (2003) Time course of early motor and neuropathological anomalies in a knock-in mouse model of Huntington’s disease with 140 CAG repeats. J Comp Neurol 465:11–26PubMedCrossRefGoogle Scholar
  59. Mihm MJ, Amann DM, Schanbacher BL, Altschuld RA, Bauer JA, Hoyt KR (2007) Cardiac dysfunction in the R6/2 mouse model of Huntington’s disease. Neurobiol Dis 25:297–308PubMedCentralPubMedCrossRefGoogle Scholar
  60. Naver B, Stub C, Moller M, Fenger K, Hansen AK, Hasholt L, Sorensen SA (2003) Molecular and behavioral analysis of the R6/1 Huntington’s disease transgenic mouse. Neuroscience 122:1049–1057PubMedCrossRefGoogle Scholar
  61. Oeda T, Shimohama S, Kitagawa N, Kohno R, Imura T, Shibasaki H, Ishii N (2001) Oxidative stress causes abnormal accumulation of familial amyotrophic lateral sclerosis-related mutant SOD1 in transgenic Caenorhabditis elegans. Hum Mol Genet 10:2013–2023PubMedCrossRefGoogle Scholar
  62. Parker JA, Connolly JB, Wellington C, Hayden M, Dausset J, Neri C (2001) Expanded polyglutamines in Caenorhabditis elegans cause axonal abnormalities and severe dysfunction of PLM mechanosensory neurons without cell death. Proc Natl Acad Sci USA 98:13318–13323PubMedCentralPubMedCrossRefGoogle Scholar
  63. Parkes TL, Elia AJ, Dickinson D, Hilliker AJ, Phillips JP, Boulianne GL (1998) Extension of Drosophila lifespan by overexpression of human SOD1 in motorneurons. Nat Genet 19:171–174PubMedCrossRefGoogle Scholar
  64. Pavese N, Andrews TC, Brooks DJ, Ho AK, Rosser AE, Barker RA, Robbins TW, Sahakian BJ, Dunnett SB, Piccini P (2003) Progressive striatal and cortical dopamine receptor dysfunction in Huntington’s disease: a PET study. Brain 126:1127–1135PubMedCrossRefGoogle Scholar
  65. Phillips JP, Campbell SD, Michaud D, Charbonneau M, Hilliker AJ (1989) Null mutation of copper/zinc superoxide dismutase in Drosophila confers hypersensitivity to paraquat and reduced longevity. Proc Natl Acad Sci USA 86:2761–2765PubMedCentralPubMedCrossRefGoogle Scholar
  66. Puls I, Jonnakuty C, LaMonte BH, Holzbaur EL, Tokito M, Mann E, Floeter MK, Bidus K, Drayna D, Oh SJ et al (2003) Mutant dynactin in motor neuron disease. Nat Genet 33:455–456PubMedCrossRefGoogle Scholar
  67. Ramesh T, Lyon AN, Pineda RH, Wang C, Janssen PM, Canan BD, Burghes AH, Beattie CE (2010) A genetic model of amyotrophic lateral sclerosis in zebrafish displays phenotypic hallmarks of motoneuron disease. Dis Model Mech 3:652–662PubMedCentralPubMedCrossRefGoogle Scholar
  68. Raslan AA, Kee Y (2013) Tackling neurodegenerative diseases: animal models of Alzheimer’s disease and Parkinson’s disease. Genes Genom 35:425–440CrossRefGoogle Scholar
  69. Ratnaparkhi A, Lawless GM, Schweizer FE, Golshani P, Jackson GR (2008) A Drosophila model of ALS: human ALS-associated mutation in VAP33A suggests a dominant negative mechanism. PLoS ONE 3:e2334PubMedCentralPubMedCrossRefGoogle Scholar
  70. Reaume AG, Elliott JL, Hoffman EK, Kowall NW, Ferrante RJ, Siwek DF, Wilcox HM, Flood DG, Beal MF, Brown RH Jr et al (1996) Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. Nat Genet 13:43–47PubMedCrossRefGoogle Scholar
  71. Reddy S, Jin P, Trimarchi J, Caruccio P, Phillis R, Murphey RK (1997) Mutant molecular motors disrupt neural circuits in Drosophila. J Neurobiol 33:711–723PubMedCrossRefGoogle Scholar
  72. Ripps ME, Huntley GW, Hof PR, Morrison JH, Gordon JW (1995) Transgenic mice expressing an altered murine superoxide dismutase gene provide an animal model of amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 92:689–693PubMedCentralPubMedCrossRefGoogle Scholar
  73. Romero E, Cha GH, Verstreken P, Ly CV, Hughes RE, Bellen HJ, Botas J (2008) Suppression of neurodegeneration and increased neurotransmission caused by expanded full-length huntingtin accumulating in the cytoplasm. Neuron 57:27–40PubMedCentralPubMedCrossRefGoogle Scholar
  74. Satyal SH, Schmidt E, Kitagawa K, Sondheimer N, Lindquist S, Kramer JM, Morimoto RI (2000) Polyglutamine aggregates alter protein folding homeostasis in Caenorhabditis elegans. Proc Natl Acad Sci USA 97:5750–5755PubMedCentralPubMedCrossRefGoogle Scholar
  75. Schiffer NW, Broadley SA, Hirschberger T, Tavan P, Kretzschmar HA, Giese A, Haass C, Hartl FU, Schmid B (2007) Identification of anti-prion compounds as efficient inhibitors of polyglutamine protein aggregation in a zebrafish model. J Biol Chem 282:9195–9203PubMedCrossRefGoogle Scholar
  76. Schilling G, Becher MW, Sharp AH, Jinnah HA, Duan K, Kotzuk JA, Slunt HH, Ratovitski T, Cooper JK, Jenkins NA et al (1999) Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Hum Mol Genet 8:397–407PubMedCrossRefGoogle Scholar
  77. Sephton CF, Good SK, Atkin S, Dewey CM, Mayer P III, Herz J, Yu G (2010) TDP-43 is a developmentally regulated protein essential for early embryonic development. J Biol Chem 285:6826–6834PubMedCentralPubMedCrossRefGoogle Scholar
  78. Shahidullah M, Le Marchand SJ, Fei H, Zhang J, Pandey UB, Dalva MB, Pasinelli P, Levitan IB (2013) Defects in synapse structure and function precede motor neuron degeneration in Drosophila models of FUS-related ALS. J Neurosci 33:19590–19598PubMedCentralPubMedCrossRefGoogle Scholar
  79. Shefner JM, Reaume AG, Flood DG, Scott RW, Kowall NW, Ferrante RJ, Siwek DF, Upton-Rice M, Brown RH Jr (1999) Mice lacking cytosolic copper/zinc superoxide dismutase display a distinctive motor axonopathy. Neurology 53:1239–1246PubMedCrossRefGoogle Scholar
  80. Shelbourne PF, Killeen N, Hevner RF, Johnston HM, Tecott L, Lewandoski M, Ennis M, Ramirez L, Li Z, Iannicola C et al (1999) A Huntington's disease CAG expansion at the murine Hdh locus is unstable and associated with behavioural abnormalities in mice. Hum Mol Genet 8:763–774Google Scholar
  81. Shelkovnikova TA, Peters OM, Deykin AV, Connor-Robson N, Robinson H, Ustyugov AA, Bachurin SO, Ermolkevich TG, Goldman IL, Sadchikova ER et al (2013) Fused in sarcoma (FUS) protein lacking nuclear localization signal (NLS) and major RNA binding motifs triggers proteinopathy and severe motor phenotype in transgenic mice. J Biol Chem 288:25266–25274PubMedCentralPubMedCrossRefGoogle Scholar
  82. Slow EJ, van Raamsdonk J, Rogers D, Coleman SH, Graham RK, Deng Y, Oh R, Bissada N, Hossain SM, Yang YZ et al (2003) Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease. Hum Mol Genet 12:1555–1567PubMedCrossRefGoogle Scholar
  83. Slow EJ, Graham RK, Osmand AP, Devon RS, Lu G, Deng Y, Pearson J, Vaid K, Bissada N, Wetzel R et al (2005) Absence of behavioral abnormalities and neurodegeneration in vivo despite widespread neuronal huntingtin inclusions. Proc Natl Acad Sci USA 102:11402–11407PubMedCentralPubMedCrossRefGoogle Scholar
  84. Southwell AL, Warby SC, Carroll JB, Doty CN, Skotte NH, Zhang WN, Villanueva EB, Kovalik V, Xie YY, Pouladi MA et al (2013) A fully humanized transgenic mouse model of Huntington disease. Hum Mol Genet 22:18–34PubMedCentralPubMedCrossRefGoogle Scholar
  85. Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, Ackerley S, Durnall JC, Williams KL, Buratti E et al (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319:1668–1672PubMedCrossRefGoogle Scholar
  86. Steffan JS, Bodai L, Pallos J, Poelman M, McCampbell A, Apostol BL, Kazantsev A, Schmidt E, Zhu YZ, Greenwald M et al (2001) Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413:739–743PubMedCrossRefGoogle Scholar
  87. Tanaka Y, Igarashi S, Nakamura M, Gafni J, Torcassi C, Schilling G, Crippen D, Wood JD, Sawa A, Jenkins NA (2006) Progressive phenotype and nuclear accumulation of an amino-terminal cleavage fragment in a transgenic mouse model with inducible expression of full-length mutant huntingtin. Neurobiol Dis 21:381–391PubMedCrossRefGoogle Scholar
  88. Tebbenkamp AT, Green C, Xu G, Denovan-Wright EM, Rising AC, Fromholt SE, Brown HH, Swing D, Mandel RJ, Tessarollo L et al (2011a) Transgenic mice expressing caspase-6-derived N-terminal fragments of mutant huntingtin develop neurologic abnormalities with predominant cytoplasmic inclusion pathology composed largely of a smaller proteolytic derivative. Hum Mol Genet 20:2770–2782PubMedCentralPubMedCrossRefGoogle Scholar
  89. Tebbenkamp AT, Swing D, Tessarollo L, Borchelt DR (2011b) Premature death and neurologic abnormalities in transgenic mice expressing a mutant huntingtin exon-2 fragment. Hum Mol Genet 20:1633–1642PubMedCentralPubMedCrossRefGoogle Scholar
  90. Teunissen CE, Steinbusch HW, Angevaren M, Appels M, de Bruijn C, Prickaerts J, de Vente J (2001) Behavioural correlates of striatal glial fibrillary acidic protein in the 3-nitropropionic acid rat model: disturbed walking pattern and spatial orientation. Neuroscience 105:153–167PubMedCrossRefGoogle Scholar
  91. Tsai KJ, Yang CH, Fang YH, Cho KH, Chien WL, Wang WT, Wu TW, Lin CP, Fu WM, Shen CK (2010) Elevated expression of TDP-43 in the forebrain of mice is sufficient to cause neurological and pathological phenotypes mimicking FTLD-U. J Exp Med 207:1661–1673PubMedCentralPubMedCrossRefGoogle Scholar
  92. Tudor EL, Galtrey CM, Perkinton MS, Lau KF, De Vos KJ, Mitchell JC, Ackerley S, Hortobagyi T, Vamos E, Leigh PN et al (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
  93. Turner BJ, Talbot K (2008) Transgenics, toxicity and therapeutics in rodent models of mutant SOD1-mediated familial ALS. Prog Neurobiol 85:94–134PubMedCrossRefGoogle Scholar
  94. Valdmanis PN, Rouleau GA (2008) Genetics of familial amyotrophic lateral sclerosis. Neurology 70:144–152PubMedCrossRefGoogle Scholar
  95. Van Raamsdonk JM, Metzler M, Slow E, Pearson J, Schwab C, Carroll J, Graham RK, Leavitt BR, Hayden MR (2007) Phenotypic abnormalities in the YAC128 mouse model of Huntington disease are penetrant on multiple genetic backgrounds and modulated by strain. Neurobiol Dis 26:189–200PubMedCrossRefGoogle Scholar
  96. Wang J, Farr GW, Hall DH, Li F, Furtak K, Dreier L, Horwich AL (2009) An ALS-linked mutant SOD1 produces a locomotor defect associated with aggregation and synaptic dysfunction when expressed in neurons of Caenorhabditis elegans. PLoS Genet 5:e1000350PubMedCentralPubMedCrossRefGoogle Scholar
  97. Watson MR, Lagow RD, Xu K, Zhang B, Bonini NM (2008) A Drosophila model for amyotrophic lateral sclerosis reveals motor neuron damage by human SOD1. J Biol Chem 283:24972–24981PubMedCentralPubMedCrossRefGoogle Scholar
  98. 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 USA 106:18809–18814PubMedCentralPubMedCrossRefGoogle Scholar
  99. Wheeler VC, Auerbach W, White JK, Srinidhi J, Auerbach A, Ryan A, Duyao MP, Vrbanac V, Weaver M, Gusella JF et al (1999) Length-dependent gametic CAG repeat instability in the Huntington’s disease knock-in mouse. Hum Mol Genet 8:115–122PubMedCrossRefGoogle Scholar
  100. Wheeler VC, White JK, Gutekunst CA, Vrbanac V, Weaver M, Li XJ, Li SH, Yi H, Vonsattel JP, Gusella JF et al (2000) Long glutamine tracts cause nuclear localization of a novel form of huntingtin in medium spiny striatal neurons in HdhQ92 and HdhQ111 knock-in mice. Hum Mol Genet 9:503–513PubMedCrossRefGoogle Scholar
  101. Williams A, Sarkar S, Cuddon P, Ttofi EK, Saiki S, Siddiqi FH, Jahreiss L, Fleming A, Pask D, Goldsmith P et al (2008) Novel targets for Huntington’s disease in an mTOR-independent autophagy pathway. Nat Chem Biol 4:295–305PubMedCentralPubMedCrossRefGoogle Scholar
  102. 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 USA 107:3858–3863PubMedCentralPubMedCrossRefGoogle Scholar
  103. Wong PC, Pardo CA, Borchelt DR, Lee MK, Copeland NG, Jenkins NA, Sisodia SS, Cleveland DW, Price DL (1995) An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron 14:1105–1116PubMedCrossRefGoogle Scholar
  104. Wu LS, Cheng WC, Hou SC, Yan YT, Jiang ST, Shen CK (2010) TDP-43, a neuro-pathosignature factor, is essential for early mouse embryogenesis. Genesis 48:56–62PubMedGoogle Scholar
  105. Yamamoto A, Lucas JJ, Hen R (2000) Reversal of neuropathology and motor dysfunction in a conditional model of Huntington’s disease. Cell 101:57–66PubMedCrossRefGoogle Scholar
  106. Yamanaka K, Miller TM, McAlonis-Downes M, Chun SJ, Cleveland DW (2006) Progressive spinal axonal degeneration and slowness in ALS2-deficient mice. Ann Neurol 60:95–104PubMedCrossRefGoogle Scholar
  107. Yang SH, Cheng PH, Banta H, Piotrowska-Nitsche K, Yang JJ, Cheng EC, Snyder B, Larkin K, Liu J, Orkin J et al (2008) Towards a transgenic model of Huntington’s disease in a non-human primate. Nature 453:921–924PubMedCentralPubMedCrossRefGoogle Scholar
  108. Yang DS, Wang CE, Zhao BT, Li W, Ouyang Z, Liu ZM, Yang HQ, Fan P, O’Neill A, Gu WW et al (2010) Expression of Huntington’s disease protein results in apoptotic neurons in the brains of cloned transgenic pigs. Hum Mol Genet 19:3983–3994PubMedCentralPubMedCrossRefGoogle Scholar
  109. Yu ZX, Li SH, Evans J, Pillarisetti A, Li H, Li XJ (2003) Mutant huntingtin causes context-dependent neurodegeneration in mice with Huntington’s disease. J Neurosci 23:2193–2202PubMedGoogle Scholar

Copyright information

© The Genetics Society of Korea 2014

Authors and Affiliations

  • Abu M. T. Islam
    • 1
  • Jina Kwak
    • 1
  • Yoo Jung Jung
    • 1
  • Yun Kee
    • 1
    • 2
  1. 1.Department of Systems Immunology, College of Biomedical ScienceKangwon National UniversityChuncheonRepublic of Korea
  2. 2.Institute of Bioscience and BiotechnologyKangwon National UniversityChuncheonRepublic of Korea

Personalised recommendations