Abstract
Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by expansion of a GAG trinucleotide repeat which codes for glutamine in the protein ataxin–1. We have investigated the effect of this expansion on ataxin–1 by immunoblot analysis. The wild–type protein is detected in both normal and affected individuals; however, a mutant protein which varies in its migration properties according to the size of the GAG repeat is detected in cultured cells and tissues from SCA1 individuals. The protein has a nuclear localization in all normal and SCA1 brain regions examined but a cytoplasmic localization of ataxin–1 was also observed in cerebellar Purkinje cells. Our data show that in SCA1, the expanded alleles are faithfully translated into proteins of apparently normal stability and distribution.
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References
Zoghbi, H.Y. The spinocerebellar degenerations. in Current Neurology (ed. Appel, S.H.) 87–110 (Mosby-Year Book, Inc., St. Louis, 1993).
Orr, H. et al. Expansion of an unstable trinucleotide (CAG) repeat in spinocerebellar ataxia type 1. Nature Genet. 4, 221–226 (1993).
Banfi, S. et al. Identification and characterization of the gene causing type 1 spinocerebellar ataxia. Nature Genet. 7, 513–519 (1994).
Willems, P.J. Dynamic mutations hit double figures. Nature Genet. 8, 213–215 (1994).
La Spada, A.R., Wilson, E.M., Lubahn, D.B., Harding, A.E. & Fischbeck, H. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352, 77–79 (1991).
A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72, 971–983 (1993).
Koide, R. et al. Unstable expansion of CAG 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 CAG trinucleotide on chromosome 12p. Nature Genet. 6, 14–18 (1994).
Burke, J.R. et al. The Haw River Syndrome: Dentatorubropallidoluysian atrophy (DRPLA) in an African-American family. Nature Genet. 7, 521–524 (1994).
Kawaguchi, Y. et al. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nature Genet. 8, 221–227 (1994).
Matilla, T., McCall, A., Subramony, S.H. & Zoghbi, H.Y. Molecular and clinical correlations in spinocerebellar ataxia type 3 and Machado-Joseph disease. Ann. Neurol. (in the press).
Quigley, C.A. et al. Complete deletion of the androgen receptor gene: definition of the null phenotype of the androgen insensitivity syndrome and determination of carrier status. J. clin. endocrinol. Metab. 74, 927–933 (1992).
Trifiro, M. et al. The 56/58 kDa androgen-binding protein in male genital skin fibroblasts with a deleted androgen receptor gene. Molec. cell. Endocrinol. 75, 37–47 (1991).
Gusella, J.F. et al. Deletion of Huntington's disease-linked G8 (D4S10) locus in Wolf-Hirschhorn syndrome. Nature 318, 75–78 (1985).
Wexler, N.S. et al. Homozygotes for Huntington's disease. Nature 326, 194–197 (1987).
Strong, T.V. et al. Widespread expression of the human and rat Huntington's disease gene in brain and nonneural tissues. Nature Genet. 5, 259–265 (1993).
Li, S.-H. et al. Huntington's disease gene (IT15) is widely expressed in human and rat tissues. Neuron 11, 985–993 (1993).
Hoogeveen, A.T et al. Characterization and localization of the Huntington disease gene product. Hum. molec. Genet. 2, 2069–2073 (1993).
Ranum, L.P.W. et al. Molecular and clinical correlations in spinocerebellar ataxia type 1 (SCA1): evidence for familial effects on the age of onset. Am. J. hum. Genet. 55, 244–252 (1994).
Mhatre, A.M. et.al. Reduced transcriptional regulatory competence of the androgen receptor in X-linked spinal and bulbar muscular atrophy. Nature Genet. 5, 184–188 (1993).
Courey, A.J. & Tijan, R. Analysis of Sp1 in vivo reveals multiple transcriptional domains, including a novel glutamine-rich activation motif. Cell 55, 887–898 (1988).
Pascal, E. & Tjian, R. Different activation domains of Sp1 govern formation of mutlimers and mediate transcriptional synergism. Genes Dev. 5, 1646–1656 (1991).
Perutz, M.F., Johnson, T., Suzuki, M. & Finch, J.T. Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases . Proc.natn. Acad. Sci. U.S.A. 91, 5355–5358 (1994).
Green, H. Human genetic diseases due to codon reiteration: relationship to an evolutionary mechanism. Cell 74, 955–956 (1993).
Laemmli, E.K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227, 680–685 (1970).
Cattoretti, G. et alAntigen unmasking on formalin-fixed, paraffin-embedded tissue sections. J. Pathol. 171, 83–98 (1993).
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Servadio, A., Koshy, B., Armstrong, D. et al. Expression analysis of the ataxin–1 protein in tissues from normal and spinocerebellar ataxia type 1 individuals. Nat Genet 10, 94–98 (1995). https://doi.org/10.1038/ng0595-94
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DOI: https://doi.org/10.1038/ng0595-94
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