YAC transgenic mice carrying pathological alleles of the MJD1 locus exhibit a mild and slowly progressive cerebellar deficit

• Published in: Human molecular genetics Vol. 11; no. 9; pp. 1075 - 1094
• Main Authors: Cemal, Cemal K., Carroll, Christopher J., Lawrence, Lorraine, Lowrie, Margaret B., Ruddle, Piers, Al-Mahdawi, Sahar, King, Rosalind H.M., Pook, Mark A., Huxley, Clare, Chamberlain, Susan
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.05.2002; Oxford Publishing Limited (England)
• Subjects: Animals; Ataxin-3; Biological and medical sciences; Blotting, Western; Cerebellum - metabolism; Cerebellum - pathology; Chromosomes, Artificial, Yeast - genetics; Classical genetics, quantitative genetics, hybrids; Demyelinating Diseases - pathology; DNA Primers - chemistry; Female; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Humans; Immunoenzyme Techniques; Machado-Joseph Disease - genetics; Machado-Joseph Disease - physiopathology; Male; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Transgenic; Mutation - genetics; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nuclear Proteins; Peptides - genetics; Polymerase Chain Reaction; Repressor Proteins; RNA, Messenger - metabolism; Transcription Factors; Trinucleotide Repeat Expansion - genetics; Vertebrata; Human; Animal model; Nervous system diseases; Joseph disease; Rodentia; Transgenic animal; Gene expression; Cerebral disorder; Genetic disease; Vertebrata; Phenotype; Mammalia; Mouse; Microsatellite DNA; Central nervous system disease; Degenerative disease; Expansion
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/11.9.1075

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.