Brain Neurorehabil.  2011 Mar;4(1):30-34. 10.12786/bn.2011.4.1.30.

Animal Models of Neurodegenerative Diseases

• Cho SR

• KMID: 1445606
• DOI: http://doi.org/10.12786/bn.2011.4.1.30

Abstract

Animal models of human diseases are essentially required to investigate the pathophysiological mechanisms of the diseases, and to test potential therapies for the clinics. However, neurodegenerative diseases including Parkinson's disease (PD) are particularly difficult to model or to recapitulate the features because most of them have multifactorial etiologies and chronically progressive symptoms, although Huntington's disease (HD) has an identified etiology such as an excessive expansion of CAG repeats. In this review, PD and HD which were typical neurodegenerative diseases were studied. The animals of PD were roughly classified into a neurotoxic model and a genetic model, and those of HD were divided into excitotoxic, transgenic, knock-in, and knock-out models. Insights obtained from these animal models of neurodegenerative diseases will guide us toward the understanding of the disease mechanisms, the design of new therapeutic strategies, and finally translation into the clinics.

Keyword

animal model; Huntington's disease; neurodegenerative disease; Parkinson's disease

MeSH Terms

Animals
Humans
Huntington Disease
Models, Animal
Models, Genetic
Neurodegenerative Diseases
Parkinson Disease

Reference

1. Cannon JR, Greenamyre JM. Neurotoxic in vivo models of Parkinson's disease: recent advances. Prog Brain Res. 2010. 184:17–33.

2. Rubinsztein D. Lesson from animal models of Huntington's disease. Trends Genet. 2002. 18:202–209.

3. Menalled L, Chesselet M. Mouse models of Huntington's disease. Trends Pharmacol Sci. 2002. 23:32–39.

4. Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K. Stages in the development of Parkinson's disease-related pathology. Cell Tissue Res. 2004. 318:121–134.

5. Carlsson A, Lindqvist M, Magnusson T, Waldeck B. On the presence of 3-hydroxytyramine in brain. Science. 1958. 127:471.

6. Ungerstedt U. 6-Hydroxy-DOPAmine induced degeneration of central monoamine neurons. Eur J Pharmacol. 1968. 5:107–110.

7. Branchi I, D'Andrea I, Armida M, Cassano T, Pèzzola A, Potenza RL, Morgese MG, Popoli P, Alleva E. Nonmotor symptoms in Parkinson's disease: investigating early-phase onset of behavioral dysfunction in the 6-hydroxydopamine-lesioned rat model. J Neurosci Res. 2008. 86:2050–2061.

8. Blandini F, Armentero MT, Martignoni E. The 6-hydroxydopamine model: News from the past. Parkinsonism Relat Disord. 2008. 14:S124–S129.

9. Langston JW, Ballard P, Tetrud JW, Irwin I. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science. 1983. 219:979–980.

10. Langston JW, Forno LS, Rebert CS, Irwin I. Selective nigral toxicity after systemic administration of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyrine (MPTP) in the squirrel monkey. Brain Res. 1984. 292:390–394.

11. Serra PA, Pluchino S, Marchetti B, Desole MS, Miele E. The MPTP mouse model: Cues on DA release and neural stem cell restorative role. Parkinsonism Relat Disord. 2008. 14:S189–S193.

12. Nicklas WJ, Vyas I, Heikkila RE. Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. Life Sci. 1985. 36:2503–2508.

13. Meredith GE, Totterdell S, Potashkin JA, Surmeier DJ. Modeling PD pathogenesis in mice: advantages of a chronic MPTP protocol. Parkinsonism Relat Disord. 2008. 14:S112–S115.

14. Sonsalla PK, Zeevalk GD, German DC. Chronic intraventricular administration of 1-methyl-4-phenylpyridinium as a progressive model of Parkinson's disease. Parkinsonism Relat Disord. 2008. 14:S116–S118.

15. Rojo AI, Montero C, Salazar M, Close RM, Fernández-Ruiz J, Sánchez-González MA, de Sagarra MR, Jackson-Lewis V, Cavada C, Cuadrado A. Persistent penetration of MPTP through the nasal route induces Parkinson's disease in mice. Eur J Neurosci. 2006. 24:1874–1884.

16. McCormack AL, Thiruchelvam M, Manning-Bog AB, Thiffault C, Langston JW, Cory-Slechta DA, Di Monte DA. Environmental risk factors and Parkinson's disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat. Neurobiol Dis. 2002. 10:119–127.

17. Heikkila RE, Nicklas WJ, Vyas I, Duvoisin RC. Dopaminergic toxicity of rotenone and the 1-methyl-4-phenylpyridinium ion after their stereotaxic administration to rats: implication for the mechanism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity. Neurosci Lett. 1985. 62:389–394.

18. Magen I, Chesselet MF. Genetic mouse models of Parkinson's disease: The state of the art. Prog Brain Res. 2010. 184:53–87.

19. 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. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science. 1997. 276:2045–2047.

20. Nance MA, Mathias-Hagen V, Breningstall G, Wick MJ, McGlennen RC. Analysis of a very large trinucleotide repeat in a patient with juvenile Huntington's disease. Neurology. 1999. 52:392–394.

21. DiFiglia M, Sapp E, Chase KO, Davies SW, Bates GP, Vonsattel JP, Aronin N. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science. 1997. 277:1990–1993.

22. Ho LW, Carmichael J, Swartz J, Wyttenbach A, Rankin J, Rubinsztein DC. The molecular biology of Huntington's disease. Psychol Med. 2001. 31:3–14.

23. Guidetti P, Charles V, Chen EY, Reddy PH, Kordower JH, Whetsell WO Jr, Schwarcz R, Tagle DA. Early degenerative changes in transgenic mice expressing mutant huntingtin involve dendritic abnormalities but no impairment of mitochondrial energy production. Exp Neurol. 2001. 169:340–350.

24. Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, Lawton M, Trottier Y, Lehrach H, Davies SW, Bates GP. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell. 1996. 87:493–506.

25. Davies SW, Turmaine M, Cozens BA, DiFiglia M, Sharp AH, Ross CA, Scherzinger E, Wanker EE, Mangiarini L, Bates GP. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell. 1997. 90:537–548.

26. Luthi-Carter R, Strand A, Peters NL, Solano SM, Hollingsworth ZR, Menon AS, Frey AS, Spektor BS, Penney EB, Schilling G, Ross CA, Borchelt DR, Tapscott SJ, Young AB, Cha JH, Olson JM. Decreased expression of striatal signaling genes in a mouse model of Huntington's disease. Hum Mol Genet. 2000. 9:1259–1271.

27. Ross CA, Tabrizi SJ. Huntington's disease: from molecular pathogenesis to clinical treatment. Lancet Neurol. 2011. 10:83–98.

28. Schilling G, Becher MW, Sharp AH, Jinnah HA, Duan K, Kotzuk JA, Slunt HH, Ratovitski T, Cooper JK, Jenkins NA, Copeland NG, Price DL, Ross CA, Borchelt DR. Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Hum Mol Genet. 1999. 8:397–407.

29. Hodgson JG, Agopyan N, Gutekunst CA, Leavitt BR, LePiane F, Singaraja R, Smith DJ, Bissada N, McCutcheon K, Nasir J, Jamot L, Li XJ, Stevens ME, Rosemond E, Roder JC, Phillips AG, Rubin EM, Hersch SM, Hayden MR. A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron. 1999. 23:181–192.

30. Levine MS, Klapstein GJ, Koppel A, Gruen E, Cepeda C, Vargas ME, Jokel ES, Carpenter EM, Zanjani H, Hurst RS, Efstratiadis A, Zeitlin S, Chesselet MF. Enhanced sensitivity to N-methyl-D-aspartate receptor activation in transgenic and knockin mouse models of Huntington's disease. J Neurosci Res. 1999. 58:515–532.

31. Smith MA, Brandt J, Shadmehr R. Motor disorder in Huntington's disease begins as a dysfunction in error feedback control. Nature. 2000. 403:544–549.

32. Nasir J, Floresco SB, OKusky JR, Diewert VM, Richman JM, Zeisler J, Borowski A, Marth JD, Phillips AG, Hayden MR. Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell. 1995. 81:811–823.

33. Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D, Conti L, MacDonald ME, Friedlander RM, Silani V, Hayden MR, Timmusk T, Sipione S, Cattaneo E. Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease. Science. 2001. 293:493–498.