Abstract
The use of model organisms is essential in order to understand the pathogenesis of many types of human disease, and this is particularly true for the study of genetic diseases such as fragile X syndrome and fragile X-associated tremor/ataxia syndrome (FXTAS). In reverse genetics, the functional study of a gene starts with the question of how a possible phenotype may derive from a specific genetic sequence (disease-causing mutation in a gene). As a first step, a gene function is purposefully altered and the effect on the normal development and/or behavior of the model organism is analyzed. In addition to providing knowledge about the cellular and molecular mechanisms underlying specific genes and their functions, animal models of human disease also provide systems for developing and validating therapeutic strategies.
The choice of which animal model is most suitable to mimic a particular disease depends on a range of factors, including anatomical, physiological, and pathological similarity; presence of orthologs of genes of interest; and conservation of basic cell biological and metabolic processes. In this chapter, we will discuss two model organisms, a mammalian vertebrate (mouse) and an invertebrate model (fly), which have been generated to study the pathogenesis of FXTAS and the effects of potential therapeutic interventions. Both mouse and fly models have proven invaluable for the study of the pathophysiology of FXTAS, including insights into the role of mutant mRNA in this disease (i.e., RNA gain-of-function mechanisms, see Chapter 6).
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References
Allen, E. G. et al. 2004. A study of the distributional characteristics of FMR1 transcript levels in 238 individuals. Hum Genet 114: 439–447.
Bacalman, S. et al. 2006. Psychiatric phenotype of the fragile X-associated tremor/ataxia syndrome (FXTAS) in males: newly described fronto-subcortical dementia. J Clin Psychiatry 67: 87–94.
Bergink, S. et al. 2006. The DNA repair-ubiquitin-associated HR23 proteins are constituents of neuronal inclusions in specific neurodegenerative disorders without hampering DNA repair. Neurobiol Dis 23: 708–716.
Bilen, J., Bonini, N. M. 2005. Drosophila as a model for human neurodegenerative disease. Annu Rev Genet 39: 153–171.
Bontekoe, C. J. M. et al. 1997. FMR1 premutation allele is stable in mice. Eur J Hum Genet 5: 293–298.
Bontekoe, C. J. et al. 2001. Instability of a (CGG)(98) repeat in the Fmr1 promoter. Hum Mol Genet 10: 1693–1699.
Bourgeois, J. A. et al. 2007. Cognitive, anxiety and mood disorders in the fragile X-associated tremor/ataxia syndrome. Gen Hosp Psychiatry 29: 349–356.
Brouwer, J. R. et al. 2007. Elevated Fmr1 mRNA levels and reduced protein expression in a mouse model with an unmethylated fragile X full mutation. Exp Cell Res 313: 244–253.
Brouwer, J. R. et al. 2008a. Altered hypothalamus-pituitary-adrenal gland axis regulation in the expanded CGG-repeat mouse model for fragile X-associated tremor/ataxia syndrome. Psychoneuroendocrinology 33: 863–873.
Brouwer, J. R. et al. 2008b. CGG-repeat length and neuropathological and molecular correlates in a mouse model for fragile X-associated tremor/ataxia syndrome. J Neurochem 107: 1671–1682.
Chan, H. Y. et al. 2002. Genetic modulation of polyglutamine toxicity by protein conjugation pathways in drosophila. Hum Mol Genet 11: 2895–2904.
Chen, Y., Tassone, F., Berman, R. F., Hagerman, P. J., Hagerman, R. J., Willemsen, R., Pessah, I. N. 2010 Jan 1. Murine hippocampal neurons expressing Fmr1 gene premutations show early developmental deficits and late degeneration. Hum Mol Genet 19(1): 196–208.
Cornish, K. M. et al. 2008. Age-dependent cognitive changes in carriers of the fragile X syndrome. Cortex 44: 628–636.
Cummings, C. J. et al. 2001. Over-expression of inducible Hsp70 chaperone suppresses neuropathology and improves motor function in SCA1 mice. Hum Mol Genet 10: 1511–1518.
de Fougerolles, A. et al. 2007. Interfering with disease: a progress report on siRNA-based therapeutics. Nat Rev Drug Discov 6: 443–453.
Entezam, A. et al. 2007. Regional FMRP deficits and large repeat expansions into the full mutation range in a new fragile X premutation mouse model. Gene 395: 125–134.
Entezam, A., Usdin, K. 2007. ATR protects the genome against CGG*CGG-repeat expansion in fragile X premutation mice. Nucleic Acids Res 36: 1050–1056.
Fernandez-Funez, P. et al. 2000. Identification of genes that modify ataxin-1-induced neurodegeneration. Nature 408: 101–106.
Greco, C. M. et al. 2002. Neuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers. Brain 125: 1760–1771.
Greco, C. M. et al. 2006. Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS). Brain 129: 243–255.
Greco, C. M. et al. 2007. Testicular and pituitary inclusion formation in fragile X associated tremor/ataxia syndrome. J Urol 177: 1434–1437.
Grigsby, J. et al. 2008. Cognitive profile of fragile X premutation carriers with and without fragile X-associated tremor/ataxia syndrome. Neuropsychology 22: 48–60.
Hagerman, R. J. et al. 2001. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 57: 127–130.
Hagerman, P. J., Hagerman, R. J. 2004. Fragile X-associated tremor/ataxia syndrome (FXTAS). Ment Retard Dev Disabil Res Rev 10: 25–30.
Handa, V. et al. 2003. The fragile X syndrome repeats form RNA hairpins that do not activate the interferon-inducible protein kinase, PKR, but are cut by dicer. Nucleic Acids Res 31: 6243–6248.
Hessl, D. et al. 2005. Abnormal elevation of FMR1 mRNA is associated with psychological symptoms in individuals with the fragile X premutation. Am J Med Genet B Neuropsychiatr Genet 139B: 115–121.
Hessl, D. et al. 2006. Amygdala dysfunction in men with the fragile X premutation. Brain 130(2): 404–416.
Hunter, J. E. et al. 2008. Investigation of phenotypes associated with mood and anxiety among male and female fragile X premutation carriers. Behav Genet 38(5): 493–502.
Iwahashi, C. et al. 2006. Protein composition of the intranuclear inclusions of FXTAS. Brain 129: 256–271.
Iyer, R. R. et al. 2000. DNA polymerase III proofreading mutants enhance the expansion and deletion of triplet repeat sequences in Escherichia coli. J Biol Chem 275: 2174–2184.
Jacquemont, S. et al. 2004. Aging in individuals with the FMR1 mutation. Am J Ment Retard 109: 154–164.
Jakupciak, J. P., Wells, R. D. 1999. Genetic instabilities in (CTG.CAG) repeats occur by recombination. J Biol Chem 274: 23468–23479.
Jin, P. et al. 2003. RNA-mediated neurodegeneration caused by the fragile X premutation rCGG repeats in drosophila. Neuron 39: 739–747.
Jin, P. et al. 2007. Pur alpha binds to rCGG repeats and modulates repeat-mediated neurodegeneration in a drosophila model of fragile X tremor/ataxia syndrome. Neuron 55: 556–564.
Jin, P., Warren, S. T. 2003. New insights into fragile X syndrome: from molecules to neurobehaviors. Trends Biochem Sci 28: 152–158.
Kazemi-Esfarjani, P., Benzer, S. 2000. Genetic suppression of polyglutamine toxicity in drosophila. Science 287: 1837–1840.
Kenneson, A. et al. 2001. Reduced FMRP and increased FMR1 transcription is proportionally associated with CGG repeat number in intermediate-length and premutation carriers. Hum Mol Genet 10: 1449–1454.
Khalili, K. et al. 2003. Pur alpha is essential for postnatal brain development and developmentally coupled cellular proliferation as revealed by genetic inactivation in the mouse. Mol Cell Biol 23: 6857–6875.
Krol, J. et al. 2007. Ribonuclease dicer cleaves triplet repeat hairpins into shorter repeats that silence specific targets. Mol Cell 25: 575–586.
Ladd, P. D. et al. 2007. An antisense transcript spanning the CGG repeat region of FMR1 is upregulated in premutation carriers but silenced in full mutation individuals. Hum Mol Genet 16: 3174–3187.
Lavedan, C. N. et al. 1997. Trinucleotide repeats (CGG)22TGG(CGG)43TGG(CGG)21 from the fragile X gene remain stable in transgenic mice. Hum Genet 100: 407–414.
Lavedan, C. et al. 1998. Long uninterrupted CGG repeats within the first exon of the human FMR1 gene are not intrinsically unstable in transgenic mice. Genomics 50: 229–240.
Louis, E. et al. 2006. Parkinsonism, dysautonomia, and intranuclear inclusions in a fragile X carrier: a clinical-pathological study. Mov Disord 27: 193–201.
Peier, A., Nelson, D. 2002. Instability of a premutation-sized CGG repeat in FMR1 YAC transgenic mice. Genomics 80: 423–432.
Primerano, B. et al. 2002. Reduced FMR1 mRNA translation efficiency in fragile X patients with premutations. RNA 8: 1–7.
Sofola, O. A. et al. 2007a. Argonaute-2 dependent rescue of a drosophila model of FXTAS by FRAXE premutation repeat. Hum Mol Genet 16: 2326–2332.
Sofola, O. A. et al. 2007b. RNA-binding proteins hnRNP A2/B1 and CUGBP1 suppress fragile X CGG premutation repeat-induced neurodegeneration in a drosophila model of FXTAS. Neuron 55: 565–571.
Tassone, F. et al. 2000. Elevated levels of FMR1 mRNA in carrier males: A new mechanism of involvement in the Fragile-X syndrome. Am J Hum Genet 66: 6–15.
Tassone, F. et al. 2004. Intranuclear inclusions in neural cells with premutation alleles in fragile X associated tremor/ataxia syndrome. J Med Genet 41: E43.
Van Dam, D. et al. 2005. Cognitive decline, neuromotor and behavioural disturbances in a mouse model for Fragile-X-associated tremor/ataxia syndrome (FXTAS). Behav Brain Res 162: 233–239.
Warrick, J. M. et al. 1998. Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in drosophila. Cell 93: 939–949.
White, P. J. et al. 1999. Stability of the human fragile X (CGG)(n) triplet repeat array in saccharomyces cerevisiae deficient in aspects of DNA metabolism. Mol Cell Biol 19: 5675–5684.
Willemsen, R. et al. 2003. The FMR1 CGG repeat mouse displays ubiquitin-positive intranuclear neuronal inclusions; implications for the cerebellar tremor/ataxia syndrome. Hum Mol Genet 12: 949–959.
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Willemsen, R., Li, Y., Berman, R.F., Brouwer, J.R., Oostra, B.A., Jin, P. (2010). Animal Models for FXTAS. In: Tassone, F., Berry-Kravis, E. (eds) The Fragile X-Associated Tremor Ataxia Syndrome (FXTAS). Springer, New York, NY. https://doi.org/10.1007/978-1-4419-5805-1_8
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DOI: https://doi.org/10.1007/978-1-4419-5805-1_8
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