Abstract
Recently, we identified a novel gene, MJD1, which contains an expanded GAG triplet repeat in Machado–Joseph disease. Here we report the induction of apoptosis in cultured cells expressing a portion of the MJD1 gene that includes the expanded GAG repeats. Cell death occurs only when the GAG repeat is translated into polyglutamine residues, which apparently precipitate in large covalently modified forms. We also created ataxic transgenic mice by expressing the expanded polyglutamine stretch in Purkinje cells. Our results demonstrate the potential involvement of the expanded polyglutamine as the common aetiological agent for inherited neurodegenerative diseases with GAG expansions.
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References
Kawaguchi, Y. et al. GAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nature Genet. 8, 221–228 (1994).
La Spada, A.R., Wilson, E.M., Lubahn, D.B., Harding, A.E. & Fischbeck, K.H. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352, 77–79 (1991).
Huntington's Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72, 971–983 (1993).
Orr, H.T. et al. Expansion of an unstable trinucleotide GAG repeat in spinocerebellar ataxia type 1. Nature Genet. 4, 221–226 (1993).
Koide, R. et al. Unstable expansion of GAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nature Genet. 6, 9–13 (1994).
Nagafuchi, S. et al. Dentatorubral and pallidoluysian atrophy expansion of an unstable GAG trinucleotide on chromosome 12p. Nature Genet. 6, 14–18 (1994).
Willems, R.J. Dynamic mutations hit double figures. Nature Genet 8, 213–215 (1994).
Housman, D. Gain of glutamines, gain of function? Nature Genet. 10, 3–4 (1995).
Maruyama, H. et al. Molecular features of the GAG repeats and clinical manifestation of Machado-Joseph disease. Hum. Mol. Genet. 4, 807–812 (1995).
Trottier, Y. et al. Cellular localization of the Huntington's disease protein and discrimination of the normal and mutated form. Nature Genet. 10, 104–110 (1995).
Sharp, A.H. et al. Widespread expression of Huntington's disease gene (IT15) protein product. Neuron 14, 1065–1074 (1995).
Servadio, A. et al. Expression analysis of the ataxin-1 protein in tissues from normal and spinocerebellar ataxia type 1 individuals. Nature Genet. 10, 94–98 (1995).
Yazawa, I. et al. Abnormal gene product identified in hereditary dentatorubral-pallidoluysian atrophy (DRPLA) brain. Nature Genet. 10, 99–103 (1995).
Trottier, Y. et al. Polyglutamine expansion as a pathological epitope in Huntington's disease and four dominant cerebellar ataxias. Nature 378, 403–405 (1995).
Burright, E.N. et al. SCA1 transgenic mice: a model for neuro-degeneration caused by an expanded CAG trinucleotide repeat. Cell 82, 937–948 (1995).
Yonehara, S., Ishii, A. & Yonehara, M. A cell-killing monoclonal antibody (anti-Fas) to a cell surface antigen co-downregulated with the receptor of tumor necrosis factor. J. Exp. Med. 169, 1747–1756 (1989).
Itoh, N. et al. The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell 66, 233–243 (1991).
Saitou, M., Narumiya, S. & Kakizuka, A. Alteration of a single amino acid residue in retinoic acid receptor causes dominant-negative phenotype. J. Bid. Chem. 269, 19101–19107 (1994).
Kawakami, H. et al. Unique features of the CAG repeats in Machado-Joseph disease. Nature Genet. 9, 344–345 (1995).
Takiyama, Y. et al. Evidence for inter-generational instability in the CAG repeat in the MJD1 gene and for conserved haplotypes at flanking markers amongst Japanese and Caucasian subjects with Machado-Joseph disease. Hum. Mol. Genet. 4, 1137–1146 (1995).
Oberdick, J., Levinthal, F. & Levinthal, C. A Purkinje cell differentiation marker shows a partial DNA sequence homology to the cellular SiS/PDGF2 gene. Neuron 1, 367–376 (1988).
Smeyne, R.J. et al. Dynamic organization of developing Purkinje cells revealed by transgene expression. Science 254, 719–721 (1991).
Bingham, P.M. et al. Stability of an expanded trinucleotide repeat in the androgen receptor gene in transgenic mice. Nature Genet 9, 191–196 (1995).
Eadie, M.J. Cerebello-olivary atrophy (Holmes type). in Handbook of Clinical Neurology, vol. 20 (eds Vinken, RJ. & Bruyn, G.W.) 403–413 (Amsterdam: North-Holland Publishing Company, 1975).
Ross, C.A. When more is less: pathogenesis of glutamine repeat neurodegenerative diseases. Neuron 15, 493–496 (1995).
Citron, M., Teplow, D.B. & Selkoe, D.J. Generation of amyloid β protein from its precursor is sequence specific. Neuron 14, 661–670 (1995).
Glenner, G.G. & Wong, C.W. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun. 120, 885–890 (1984).
Goldgaber, D. et al. Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer's disease. Science 235, 877–880 (1987).
Kang, J. et al. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature 325, 733–736 (1987).
Alzheimer, A. Über eine eigenatige Erkrankung der Hirnrinde. Zbl Nervenheik 30, 177–179 (1907).
Mayeux, R. & Chun, M.R. Acquired and hereditary dementias. in Merritt's Textbook of Neurology, 9th edn. (ed. Rowland, L.R) (Baltimore: Williams &Wilkins, 1995).
Green, H. Human genetic diseases due to codon reiteration: relationship to an evolutionary mechanism. Cell 74, 955–956 (1993).
Chou, P.Y. & Fasman, G.D. Prediction of the secondary structure of proteins from their amino acid sequence. Adv. Enzymol. 47, 45–148 (1978).
Perutz, M.F., Johnson, T., Suzuki, M. & Finch, J.T. Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases. Proc. Natl. Acad. Sci. USA 91, 5355–5358 (1994).
Prusiner, S.B. & Hsiao, K.K. Human prion diseases. Ann. Neurol. 35, 385–395 (1994).
Pan, K.-M. et al. Conversion of a-helices into (β-sheets features in the formation of the scrapie prion proteins. Proc. Natl. Acad. Sci. USA 90, 10962–10966 (1993).
Kakizuka, A. et al. Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RARα with a novel putative transcription factor, PML. Cell 66, 663–674 (1991).
Umesono, K., Murakami, K.K., Thompson, C.C. & Evans, R.M. Direct repeats as selective response elements for the thyroid hormone, retinoic acid, and vitamin D3 receptors. Cell 65, 1255–1266 (1991).
Kozak, M. An analysis of 5′-noncoding sequences from 699 vertebrate messenger RNAs. Nucl. Acids Res. 15, 8125–8148 (1987).
Field, J. et al. Purification of a RAS-responsive adenylyl cyclase complex from Saccharomyces cerevisiae by use of an epitope addition method. Mol. Cell. Biol. 8, 2159–2165 (1988).
Kakizuka, A., Kitamura, N. & Nakanishi, S. Localization of DNA sequences governing alternative mRNA production of rat kininogen genes. J. Biol. Chem. 263, 3884–3892 (1988).
Kakizuka, A., Ingi, T., Murai, T. & Nakanishi, S. A set of U1 snRNA-complementary sequences involved in governing alternative RNA splicing of the kininogen genes. J. Biol. Chem. 265, 10102–10108 (1990).
Yamaguchi, M. et al. Down-regulation of interleukin 6 receptors of mouse myelomonocytic leukemic cells by leukemia inhibitory factor. J. Biol. Chem. 267, 22035–22042 (1992).
Sanes, J.R., Rubenstein, J.L.R. & Nicolas, J.-F. Use of a recombinant retrovirus to study post-implantation cell lineage in mouse embryos. EMBO J. 5, 3133–3142 (1986).
Saitou, M. et al. Inhibition of skin development by targeted expression of a dominant-negative retinoic acid receptor. Nature 374, 159–162 (1995).
Mizushima, S. & Nagata, S. pEF-BOS, a powerful mammalian expression vector. Nucl. Acids Res. 18, 5322 (1990).
Dyck, J.A. et al. A novel macromolecular structure is a target of the promyelocyte-retinoic acid receptor oncoprotein. Cell 76, 333–343 (1994).
Ishida, Y., Agata, Y., Shibahara, K. & Honjo, T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 11, 3887–3895 (1992).
Rösl, F. A simple and rapid method for detection of apoptosis in human cells.Nucl. Acids Res. 20, 5243 (1992).
Vandaele, S. et al. Purkinje cell protein-2 regulatory regions and transgene expression in cerebellar compartments. Genes Dev. 5, 1136–1148 (1991).
Kakizuka, A. et al. A mouse cdc25 homolog is differentially and developmental expressed. Genes Dev. 6, 578–590 (1992).
Gordon, J.W. Production of transgenic mice. in Guide to Techniques in Mouse Development (eds Wassarman, P. M. & DePamphilis, M.L.) 747–771 (San Diego: Academic, 1993).
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Ikeda, H., Yamaguchi, M., Sugai, S. et al. Expanded polyglutamine in the Machado–Joseph disease protein induces cell death in vitro and in vivo. Nat Genet 13, 196–202 (1996). https://doi.org/10.1038/ng0696-196
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DOI: https://doi.org/10.1038/ng0696-196
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