Human Molecular Genetics, 2002, Vol. 11, No. 9 1075-1094
© 2002 Oxford University Press
YAC transgenic mice carrying pathological alleles of the MJD1 locus exhibit a mild and slowly progressive cerebellar deficit
1Cell and Molecular Biology, 2Leukocyte Biology and 3Biological Structure and Function, Division of Biomedical Sciences, Faculty of Medicine, Sir Alexander Fleming Building, Imperial College, London SW7 2AZ, UK and 4Royal Free and University College Medical School, Neurosciences, Rowland Hill Street, London NW3 2PF, UK
Machado–Joseph disease (MJD; MIM 109150) is a late-onset neurodegenerative disorder caused by the expansion of a polyglutamine tract within the MJD1 gene. We have previously reported the generation of human yeast artificial chromosome (YAC) constructs encompassing the MJD1 locus into which expanded (CAG)76 and (CAG)84 repeat motifs have been introduced by homologous recombination. Transgenic mice containing pathological alleles with polyglutamine tract lengths of 64, 67, 72, 76 and 84 repeats, as well as the wild type with 15 repeats, have now been generated using these YAC constructs. The mice with expanded alleles demonstrate a mild and slowly progressive cerebellar deficit, manifesting as early as 4 weeks of age. As the disease progresses, pelvic elevation becomes markedly flattened, accompanied by hypotonia, and motor and sensory loss. Neuronal intranuclear inclusion (NII) formation and cell loss is prominent in the pontine and dentate nuclei, with variable cell loss in other regions of the cerebellum from 4 weeks of age. Interestingly, peripheral nerve demyelination and axonal loss is detected in symptomatic mice from 26 weeks of age. In contrast, transgenic mice carrying the wild-type (CAG)15 allele of the MJD1 locus appear completely normal at 20 months. Disease severity increases with the level of expression of the expanded protein and the size of the repeat. These mice are representative of MJD and will be a valuable resource for the detailed analysis of the roles of repeat length, tissue specificity and level of expression in the neurodegenerative processes underlying MJD pathogenesis.
* To whom correspondence should be addressed. Tel: +44 20 7594 3235; Fax: +44 20 7594 3015; Email: c.cemal{at}ic.ac.uk
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. Boy, T. Schmidt, H. Wolburg, A. Mack, S. Nuber, M. Bottcher, I. Schmitt, C. Holzmann, F. Zimmermann, A. Servadio, et al. Reversibility of symptoms in a conditional mouse model of spinocerebellar ataxia type 3 Hum. Mol. Genet., November 15, 2009; 18(22): 4282 - 4295. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Chen, T.-S. Tang, H. Tu, O. Nelson, M. Pook, R. Hammer, N. Nukina, and I. Bezprozvanny Deranged Calcium Signaling and Neurodegeneration in Spinocerebellar Ataxia Type 3 J. Neurosci., November 26, 2008; 28(48): 12713 - 12724. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Alves, E. Regulier, I. Nascimento-Ferreira, R. Hassig, N. Dufour, A. Koeppen, A. L. Carvalho, S. Simoes, M. C. P. de Lima, E. Brouillet, et al. Striatal and nigral pathology in a lentiviral rat model of Machado-Joseph disease Hum. Mol. Genet., July 15, 2008; 17(14): 2071 - 2083. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Bichelmeier, T. Schmidt, J. Hubener, J. Boy, L. Ruttiger, K. Habig, S. Poths, M. Bonin, M. Knipper, W. J. Schmidt, et al. Nuclear Localization of Ataxin-3 Is Required for the Manifestation of Symptoms in SCA3: In Vivo Evidence J. Neurosci., July 11, 2007; 27(28): 7418 - 7428. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Haacke, F. U. Hartl, and P. Breuer Calpain Inhibition Is Sufficient to Suppress Aggregation of Polyglutamine-expanded Ataxin-3 J. Biol. Chem., June 29, 2007; 282(26): 18851 - 18856. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Ellisdon, B. Thomas, and S. P. Bottomley The Two-stage Pathway of Ataxin-3 Fibrillogenesis Involves a Polyglutamine-independent Step J. Biol. Chem., June 23, 2006; 281(25): 16888 - 16896. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Goti, S. M. Katzen, J. Mez, N. Kurtis, J. Kiluk, L. Ben-Haiem, N. A. Jenkins, N. G. Copeland, A. Kakizuka, A. H. Sharp, et al. A Mutant Ataxin-3 Putative-Cleavage Fragment in Brains of Machado-Joseph Disease Patients and Transgenic Mice Is Cytotoxic above a Critical Concentration J. Neurosci., November 10, 2004; 24(45): 10266 - 10279. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Griffin, C. K. Cemal, and M. A. Pook Defining a metabolic phenotype in the brain of a transgenic mouse model of spinocerebellar ataxia 3 Physiol Genomics, February 13, 2004; 16(3): 334 - 340. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Michalik and C. Van Broeckhoven Pathogenesis of polyglutamine disorders: aggregation revisited Hum. Mol. Genet., October 15, 2003; 12(90002): R173 - 186. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. M. Miller, H. Xia, G. L. Marrs, C. M. Gouvion, G. Lee, B. L. Davidson, and H. L. Paulson Allele-specific silencing of dominant disease genes PNAS, June 10, 2003; 100(12): 7195 - 7200. [Abstract] [Full Text] [PDF]
|
|