Abstracts
Résumé
La chorée de Huntington est une maladie neurodégénérative héréditaire dominante, caractérisée par l’apparition progressive d’une dyskinésie, de déficits cognitifs et de troubles émotionnels. Près d’une décennie après l’identification du gène et de la mutation responsable de cette maladie, celle-ci reste incurable. Néanmoins, le développement de modèles transgéniques a permis une avancée majeure dans la connaissance des mécanismes cellulaires et moléculaires précoces de la maladie. La mutation conduirait à un dérèglement de la transcription, à une altération de la dégradation des protéines défectueuses par les protéasomes, ainsi qu’à des processus excitotoxiques et à un dysfonctionnement des mitochondries. Cet article souligne les apports récents de l’utilisation de modèles transgéniques chez la souris et chez la drosophile dans la compréhension de la pathogénie et dans l’élaboration de nouvelles stratégies thérapeutiques.
Summary
Huntington’s disease is an hereditary dominant neurodegenerative disorder clinically characterised by progressive dyskinesia, cognitive decline and psychiatric disturbances. One decade after the identification of the gene whose mutation is responsible for the disease, this pathology remains incurable. However, major insights into early cellular and molecular basis of Huntington’s disease have arisen from transgenic models. Transcriptional dysregulation, abnormal degradation of misfolded proteins as well as excitotoxic processes and mitochondrial dysfunction are involved in Huntington’s disease. The present review discusses the recent insights gained from mouse and Drosophila models towards the understanding of pathogenesis and the development of new therapeutic tools.
Appendices
Références
- 1. The Huntington’s disease collaborative research group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 1993; 72: 971-83.
- 2. Mangiarini L, Sathasivam K, Seller M, et al. 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.
- 3. Davies SW, Turmaine M, Cozens BA, et al. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 1997; 90: 537-48.
- 4. Reddy PH, Williams M, Charles V, et al. Behavioural abnormalities and selective neuronal loss in HD transgenic mice expressing mutated full-length HD cDNA. Nat Genet 1998; 20: 198-202.
- 5. Hodgson JG, Agopyan N, Gutekunst CA, et al. A YAC mouse model for Huntington’s disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron 1999; 23: 181-92.
- 6. Lin CH, Tallaksen-Greene S, Chien WM, et al. Neurological abnormalities in a knock-in mouse model of Huntington’s disease. Hum Mol Genet 2001; 10: 137-44.
- 7. Menalled LB, Sison JD, Wu Y, et al. Early motor dysfunction and striosomal distribution of huntingtin microaggregates in Huntington’s disease knock-in mice. J Neurosci 2002; 22: 8266-76.
- 8. Wheeler VC, Gutekunst CA, Vrbanac V, et al. Early phenotypes that presage late-onset neurodegenerative disease allow testing of modifiers in Hdh CAG knock-in mice. Hum Mol Genet 2002; 11: 633-40.
- 9. Steffan JS, Bodai L, Pallos J, et al. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 2001; 413: 739-43.
- 10. Kazantsev A, Walker HA, Slepko N, et al. A bivalent Huntingtin binding peptide suppresses polyglutamine aggregation and pathogenesis in Drosophila. Nat Genet 2002; 30: 367-76.
- 11. Jackson GR, Salecker I, Dong X, et al. Polyglutamine-expanded human huntingtin transgenes induce degeneration of Drosophila photoreceptor neurons. Neuron 1998; 21: 633-42.
- 12. Kazemi-Esfarjani P, Benzer S. Genetic suppression of polyglutamine toxicity in Drosophila. Science 2000; 287: 1837-40.
- 13. Marsh JL, Walker H, Theisen H, et al. Expanded polyglutamine peptides alone are intrinsically cytotoxic and cause neurodegeneration in Drosophila. Hum Mol Genet 2000; 9:13-25.
- 14. Perutz MF, Johnson T, Suzuki M, Finch JT. Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases. Proc Natl Acad Sci USA 1994; 91: 5355-8.
- 15. Green H. Human genetic diseases due to codon reiteration: relationship to an evolutionary mechanism. Cell 1993; 74: 955-6.
- 16. Cooper AJ, Jeitner TM, Gentile V, Blass JP. Cross linking of polyglutamine domains catalyzed by tissue transglutaminase is greatly favored with pathological-length repeats: does transglutaminase activity play a role in (CAG)(n)/Q(n)-expansion diseases? Neurochem Int 2002; 40: 53-67.
- 17. Mastroberardino PG, Iannicola C, Nardacci R, et al. Tissue transglutaminase ablation reduces neuronal death and prolongs survival in a mouse model of Huntington’s disease. Cell Death Differ 2002; 9: 873-80.
- 18. McCampbell A, Taylor JP, Taye AA, et al. CREB-binding protein sequestration by expanded polyglutamine. Hum Mol Genet 2000; 9: 2197-202.
- 19. Jana NR, Tanaka M, Wang G, Nukina N. Polyglutamine length-dependent interaction of Hsp40 and Hsp70 family chaperones with truncated N-terminal huntingtin: their role in suppression of aggregation and cellular toxicity. Hum Mol Genet 2000; 9: 2009-18.
- 20. Levine MS, Klapstein GJ, Koppel A, et al. Enhanced sensitivity to N-methyl-D-aspartate receptor activation in transgenic and knock-in mouse models of Huntington’s disease. J Neurosci Res 1999; 58: 515-32.
- 21. Cha JH. Transcriptional dysregulation in Huntington’s disease. Trends Neurosci 2000; 23: 387-92.
- 22. Liévens J, Woodman B, Mahal A, Bates G. Abnormal phosphorylation of synapsin I predicts a neuronal transmission impairment in the R6/2 Huntington’s disease transgenic mice. Mol Cell Neurosci 2002; 20: 638-48.
- 23. Liévens JC, Woodman B, Mahal A, et al. Impaired glutamate uptake in the R6 Huntington’s disease transgenic mice. Neurobiol Dis 2001; 8: 807-21.
- 24. Ferrante RJ, Andreassen OA, Dedeoglu A, et al. Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington’s disease. J Neurosci 2002; 22: 1592-9.
- 25. Rosas HD, Koroshetz WJ, Jenkins BG, et al. Riluzole therapy in Huntington’s disease. Mov Disord 1999; 14: 326-30.
- 26. Tabrizi SJ, Cleeter MW, Xuereb J, et al. Biochemical abnormalities and excitotoxicity in Huntington’s disease brain. Ann Neurol 1999; 45: 25-32.
- 27. Laforet GA, Sapp E, Chase K, et al. Changes in cortical and striatal neurons predict behavioral and electrophysiological abnormalities in a transgenic murine model of Huntington’s disease. J Neurosci 2001; 21: 9112-23.
- 28. Schilling G, Becher MW, Sharp AH, et al. Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Hum Mol Genet 1999; 8: 397-407.
- 29. Shelbourne PF, Killeen N, Hevner RF, et al. A Huntington’s disease CAG expansion at the murine Hdh locus is unstable and associated with behavioural abnormalities in mice. Hum Mol Genet 1999; 8: 763-74.
- 30. Yamamoto A, Lucas JJ, Hen R. Reversal of neuropathology and motor dysfunction in a conditional model of Huntington’s disease. Cell 2000; 101: 57-66.