Abstract
Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by expansion of a polyglutamine tract in ataxin-1. In affected neurons of SCA1 patients and transgenic mice, mutant ataxin-1 accumulates in a single, ubiquitin-positive nuclear inclusion. In this study, we show that these inclusions stain positively for the 20S proteasome and the molecular chaperone HDJ-2/HSDJ. Similarly, HeLa cells transfected with mutant ataxin-1 develop nuclear aggregates which colocalize with the 20S proteasome and endogenous HDJ-2/HSDJ. Overexpression of wild-type HDJ-2/HSDJ in HeLa cells decreases the frequency of ataxin-1 aggregation. These data suggest that protein misfolding is responsible for the nuclear aggregates seen in SCA1, and that overexpression of a DnaJ chaperone promotes the recognition of a misfolded polyglutamine repeat protein, allowing its refolding and/or ubiquitin-dependent degradation.
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References
Wisniewski, T., Ghiso, J. & Frangione, B. Biology of A beta amyloid in Alzheimer's disease. Neurobiol. Dis. 4, 313â328 (1997)
Polymeropoulos, M.H. et al. Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease. Science 276, 2045â2047 (1997)
Prusiner, S.B. Prion diseases and the BSE crisis. Science 278, 245â251 (1997)
Davies, S.W. et al. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90, 537â548 (1997)
DiFiglia, M. et al. Aggregation of Huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277, 1990â1993 (1997)
Igarashi, S. et al. Suppression of aggregate formation and apoptosis by transglutaminase inhibitors in cells expressing truncated DRPLA protein with an expanded polyglutamine stretch. Nature Genet. 18, 111â117 (1998)
Skinner, P.J. et al. Ataxin-1 with extra glutamines induces alterations in nuclear matrix-associated structures. Nature 389, 971â974 (1997)
Paulson, H.L. et al. Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia Type 3. Neuron 19, 333â334 (1997)
Zoghbi, H.Y. & Orr, H.T. Spinocerebellar ataxia type 1. Semin. Cell Biol. 6, 29â35 (1995)
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, 5355â5358 (1994)
Stott, K., Blackburn, J.M., Butler, P.J.G. & Perutz, M. Incorporation of glutamine repeats makes protein oligomerize: Implications for neurodegenerative diseases. Proc. Natl. Acad. Sci. USA 92, 6509â6513 (1995)
Hershko, A. & Ciechanover, A. The ubiquitin system for protein degradation. Annu. Rev. Biochem. 61, 761 â807 (1992)
Hochstrasser, M. Ubiquitin-dependent protein degradation. Annu. Rev. Genet. 30, 405â439 (1996)
Adams, G.M. et al. Structural and Functional Effects of PA700 and Modular Protein on Proteasomes . J. Mol. Biol. 273, 646â657 (1997)
Coux, O., Tanaka, K. & Goldberg, A.L. Structure and functions of the 20S and 26S proteasomes . Annu. Rev. Biochem. 65, 801â847 (1996)
Bush, K.T., Goldberg, A.L. & Nigam, S.K. Proteasome Inhibition Leads to a Heat-shock Response, Induction of Endoplasmic Reticulum Chaperones, and Thermotolerance. J. Biol. Chem. 272, 9086â9092 (1997)
Zhou, M., Wu, X. & Ginsberg, H.N. Evidence that a rapidly turning over protein, normally degraded by proteasomes, regulates hsp72 gene transcription in HepG2 cells. J. Biol. Chem. 271, 247â269 ( 1996)
Lee, D.H. & Goldberg, A.L. Proteasome Inhibitors Cause Induction of Heat Shock Proteins and Trehalose, Which Together Confer Thermotolerance in Saccharomyces cerevisiae. Mol. Cell. Biol. 18, 30â38 (1998)
Bukau, B. & Horwich, A.L. The Hsp70 and Hsp60 Chaperone Machines . Cell 92, 351â366 (1998)
Lu, Z. & Cyr, D.M. The Conserved Carboxyl Terminus and Zinc Finger-Like Domain of the Co-chaperone Ydj1 Assist Hsp70 in Protein Folding . J. Biol. Chem. 273, 5970â5978 (1998)
Hartl, F.U. Molecular chaperones in cellular protein folding. Nature 381, 571â580 (1996)
Hendricks, J.P. & Hartl, F. -U.Molecular chaperone functions of heat shock proteins. Annu. Rev. Biochem. 62, 349â384 (1993)
Sherman, M.Y. & Goldberg, A.L. Involvement of chaperonin dnaK in the rapid degradation of a mutant protein in Escherichia coli. EMBO J. 11, 71â77 ( 1992)
Straus, D.B., Walter, W.A. & Gross, C.A. Escherichia coli heat shock gene mutants are defective in proteolysis . Genes Dev. 2, 1851â1858 (1988)
Johnson, E.S., Bartel, B., Seufert, W. & Varshavsky, V. Ubiquitin as a degradation signal. EMBO J. 11, 497â505 (1992)
Lee, D.H., Sherman, M.Y. & Goldberg, A.L. Involvement of the Molecular Chaperone Ydj1 in the Ubiquitin-Dependent Degradation of Short-Lived and Abnormal Proteins in Saccharomyces cerevisiae. Mol. Cell. Biol. 16, 4773â4781 (1996)
Burright, E.N. et al. SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat. Cell 82, 937â948 (1995)
Attaix, D. et al. Expression of subunits of the 19S complex and of the PA28 activator in rat skeletal muscle. Mol. Biol. Rep. 24, 95â98 (1997)
Chellaiah, A., Davis, A. & Mohanakumar, T. Cloning of a unique human homologue of the Escherichia coli DANJ heat shock protein. Biochim. Biophys. Acta 1174, 111â113 (1993)
Oh, S., Iwahori, A. & Kato, S. Human cDNA encoding DnaJ protein homologue. Biochim. Biophys. Acta 1174, 114â116 ( 1993)
Cyr, D.M., Lu, X. & Douglas, M.G. Regulation of Hsp70 function by a eukaryotic DnaJ homolog. J. Biol. Chem. 267, 20927â20931 ( 1992)
Tang, Y., Ramakrishnan, C., Thomas, J. & DeFranco, D.B. A Role for HDJ-2/HSDJ in Correcting Subnuclear Trafficking, Transactivation, and Transrepression Defects of a Glucocorticoid Receptor Zinc Finger Mutant. Mol. Biol. Cell 8, 795â809 ( 1997)
Schirmer, E.C. & Lindquist, S. Interactions of the chaperone Hsp104 with yeast Sup35 and mammalian PrP. Proc. Natl. Acad. Sci. USA 94, 13932â13937 ( 1997)
DebBurman, S.K., Raymond, G.J., Caughey, B. & Lindquist, S. Chaperone-supervised conversion of prion protein to its protease-resistant form. Proc. Natl. Acad. Sci. USA 94, 13938 â13943 (1997)
Welch, W.J. & Gambetti, P. Chaperoning Brain Diseases. Nature 392, 23â24 ( 1998)
Chernoff, Y.O., Lindquist, S.L., Ono, B., Inge-Vechtomov, S.G. & Liebman, S.W. Role of the Chaperone Protein Hsp104 in Propagation of the Yeast Prion-Like Factor [psi+]. Science 268, 880â883 (1995)
Cyr, D.M., Langer, T. & Douglas, M.G. DnaJ-like proteins: molecular chaperones and specific regulators of Hsp70 . Trends Biochem. Sci. 19, 176â181 (1994)
Dienel, G., Kiessling, M., Soubrie, P., Bockaert, J. & Pin, J. Synthesis of heat shock proteins in rat brain cortex after transient ischemia. J. Cereb. Blood Flow Metab. 6, 505â510 (1986)
Brown, I.R. Induction of heat shock (stress) genes in the mammalian brain by hyperthermia and other traumatic events: a current perspective. J. Neurosci. Res. 27, 247â255 (1990)
Cyr, D.M. Cooperation of the molecular chaperone Ydj1 with specific Hsp70 homologs to suppress protein aggregation. FEBS Lett. 359, 129â132 (1995)
Schumacher, R.J. et al. Cooperative action of Hsp70, Hsp90, and DnaJ proteins in protein renaturation . Biochemistry 35, 14889â14898 (1996)
Matilla, T. et al. The cerebellar leucine rich acidic nuclear protein interacts with ataxin-1 . Nature 389, 974â978 (1997)
Shibatani, T. & Ward, W.F. Sodium dodecyl sulfate (SDS) activation of the 20S proteasome in rat liver. Arch. Biochem. Biophys. 321, 160â166 (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, 94â98 (1995)
Acknowledgements
We thank W.F. Ward for the anti-proteasome antisera, G.N. DiMartino for anti-PA700 and anti-P31 antisera, J. K. Dunn for advice on statistical analyses, A.L. Beaudet, O.Lichtarge and W.E. O'Brien for their critical reading of the manuscript, and V. Brandt for her editorial help. This work is supported by grant from the National Institutes of Heath (NS27699 and NS22920) and by the Baylor Mental Retardation Research Center. H.Y.Z. is a Howard Hughes Medical Institute Investigator.
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Cummings, C., Mancini, M., Antalffy, B. et al. Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1. Nat Genet 19, 148â154 (1998). https://doi.org/10.1038/502
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DOI: https://doi.org/10.1038/502
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