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Role of heat shock proteins during polyglutamine neurodegeneration

Mechanisms and hypothesis

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Abstract

A common feature of many neurodegenerative diseases, including Alzheimer’s and Parkinsons’s disease, the prion disorders, and the CAG repeat polyglutamine (polyQ) diseases, is the occurrence of protein aggregates within or outside of nerve cells. Molecular chaperones such as heat shock proteins (HSPs) have been proposed to play a critical role in preventing the accumulation of misfolded proteins that lead to the deposition of aggregates during pathology. This article focuses on the role of HSPs during polyQ pathologies, which include Huntington’s disease, spinal and bulbar muscular atrophy, dentatorubral and pallidoluysian atrophy, and several forms of spinocerebellar ataxia. Recently, unifying mechanisms that are involved during polyQ disease have emerged, such as abnormal transcription, impaired degradation systems, and interference of a polyQ expansion with neuronal survival and death-signaling pathways like the activation of caspases and kinases. This article reviews recent studies that point to the involvement of these mechanisms during polyQ pathology and discusses how HSPs can interfere with such processes by paying special attention to HSPs as modulators of survival and death-signaling pathways.

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References

  • Adachi H., Katsuno M., Minamiyama M., Sang C., Pagoulatos G., Angelidis C., et al. (2003) Heat shock protein 70 chaperone overexpression ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model by reducing nuclear-localized mutant androgen receptor protein. J. Neurosci. 23, 2203–2211.

    PubMed  CAS  Google Scholar 

  • Agarraberes F. A. and Dice J. F. (2001) A molecular chaperone complex at the lysosomal membrane is required for protein translocation. J. Cell Sci. 114, 2491–2499.

    PubMed  CAS  Google Scholar 

  • Alberti S. and Hohfeld J. (2002) Molecular chaperones in the regulation of signal transduction. Ann. N. Y. Acad. Sci. 973, 3,4.

    Article  PubMed  CAS  Google Scholar 

  • Alberti S., Demand J., Esser C., Emmerich N., Schild H., and Hohfeld J. (2002) Ubiquitylation of BAG-1 suggests a novel regulatory mechanism during the sorting of chaperone substrates to the proteasome. J. Biol. Chem. 277, 45920–45927.

    Article  PubMed  CAS  Google Scholar 

  • Arrigo A.-P. (1998) Small stress proteins: chaperones that act as regulators of intracellular redox state and programmed cell death. Biol. Chem. 379, 19–26.

    PubMed  CAS  Google Scholar 

  • Ashkenazi A. and Dixit V. M. (1998) Death receptor: signaling and modulation. Science 281, 1305–1308.

    Article  PubMed  CAS  Google Scholar 

  • Bailey C. K., Andriola I. F. M., Kampinga H. H., and Merry D. E. (2002) Molecular chaperones enhance the degradation of expanded polyglutamine repeat androgen receptor in a cellular model of spinal and bulbar muscular atrophy. Hum. Mol. Genet. 11, 515–523.

    Article  PubMed  CAS  Google Scholar 

  • Beal M. F. (2000) Energetics in the pathogenesis of neurodegenerative diseases. Trends Neurosci. 23, 298–304.

    Article  PubMed  CAS  Google Scholar 

  • Beere H. M., Wolf B. B., Cain K., Mosser D. D., Mahboubi A., Kuwana T., et al. (2000) Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nat. Cell Biol. 2, 469–475.

    Article  PubMed  CAS  Google Scholar 

  • Bence N. F., Roopal M., and Kopito R. R. (2001) Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292, 1552–1555.

    Article  PubMed  CAS  Google Scholar 

  • Benn S. C., Perrelet D., Kato A. C., Scholz J., Decosterd I., Mannion R. J., et al. (2002) Hsp27 upregulation and phosphorylation is required for injured sensory and motor neurons survival. Neuron 36, 45–56.

    Article  PubMed  CAS  Google Scholar 

  • Ben-Zvi A. P. and Goloubinoff P. (2001) Mechanisms of disaggregation and refolding of stable protein aggregates by molecular chaperones. J. Struct. Biol. 135, 84–93.

    Article  PubMed  CAS  Google Scholar 

  • Bercovich B, Stancovski I., Mayer A., Blumenfeld N., Laszlo A., Schwartz A. L., and Ciechanover A. (1997) Ubiquitin-dependent degradation of certain protein substrates in vitro requires the molecular chaperone Hsc70. J. Biol. Chem. 272, 9002–9010.

    Article  PubMed  CAS  Google Scholar 

  • Brazil D. P., Park J., and Hemmings B. A. (2002) PKB binding proteins. Getting on the Akt. Cell 111, 293–303.

    Article  PubMed  CAS  Google Scholar 

  • Browne S. E., Ferrante R. J., and Beal M. F. (1999) Oxidative stress in Huntington’s disease. Brain Pathol. 9, 147–163.

    Article  PubMed  CAS  Google Scholar 

  • Bruey J. M., Ducasse C., Bonniaud P., Ravagnan L., Susin S. A., Diaz-Latoud C., et al. (2000) Hsp27 negatively regulates cell death by interacting with cytochrome c. Nat. Cell Biol. 2, 645–652.

    Article  PubMed  CAS  Google Scholar 

  • Burnett B., Li F., and Pittman R. N. (2003) The polyglutamine neurodegenerative protein ataxin-3 binds polyubiquitylated proteins and has ubiquitin protease activity. Hum. Mol. Genet. 12, 3195–3205.

    Article  PubMed  CAS  Google Scholar 

  • Busch A., Engemann S., Lurz R., Okazawa H., Lehrach H., and Wanker E. E. (2003) Mutant huntingtin promotes the fibrillogenesis of wild-type huntingtin: a potential mechanism for loss of huntingtin function in Huntington’s disease. J. Biol. Chem. 278, 41452–41461.

    Article  PubMed  CAS  Google Scholar 

  • Carmichael J., Chatellier J., Woolfson A., Milstein C., Fersht A. R., and Rubinsztein D. C. (2001) Bacterial and yeast chaperones reduce both aggregate formation and cell death in mammalian cell models of Huntington’s disease. Proc. Natl. Acad. Sci. U. S. A. 97, 9701–9705.

    Article  Google Scholar 

  • Carmichael J., Sugars K. L., Bao Y. P., and Rubinsztein D. C. (2002) Glycogen synthase kinase-3β inhibitors prevent cellular polyglutamine toxicity caused by the Huntington’s disease mutation. J. Biol. Chem. 277, 33791–33798.

    Article  PubMed  CAS  Google Scholar 

  • Cha J. H., Frey A. S., Alsdorf S. A., Kerner J. A., Kosinski C. M., Mangiarini L., et al. (1999) Altered neurotransmitter receptor expression in transgenic mouse models of Huntington’s disease. Philos. Trans. R. Soc. Lond. B Biol. Sci. 354, 981–989.

    Article  PubMed  CAS  Google Scholar 

  • Chai Y., Berke S. S., Cohen R. E., and Paulson H. L. (2003) Poly-ubiquitin binding by the polyglutamine disease protein ataxin-3 links its normal function to protein surveillance pathways. J. Biol. Chem. 279, 3605–3611.

    Article  PubMed  CAS  Google Scholar 

  • Chai Y., Koppenhafer S. L., Bonini N. M., and Paulson H. L. (1999) Analysis of the role of heat shock protein (Hsp) molecular chaperones in polyglutamine disease. J. Neurosci. 19, 10338–10347.

    PubMed  CAS  Google Scholar 

  • Chan E. Y., Luthi-Carter R., Strand A., Solano S. M., Hanson S. A., DeJohn M. M., et al. (2002) Increased huntingtin protein length reduces the number of polyglutamine-induced gene expression changes in mouse models of Huntington’s disease. Hum. Mol. Gent. 11, 1939–1951.

    Article  CAS  Google Scholar 

  • Chan H. Y., Warrick J. M., Andriola I., Merry D., and Bonini N. M. (2002) Genetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila. Hum. Mol. Genet. 11, 2895–2904.

    Article  PubMed  CAS  Google Scholar 

  • Chan H. Y., Warrick J. M., Gray-Board G. L., Paulson H. L., and Bonini N. M. (2000) Mechanisms of chaperone suppression of polyglutamine disease: selectivity, synergy and modulation of protein solubility in Drosophila. Hum. Mol. Genet. 9, 2811–2820.

    Article  PubMed  CAS  Google Scholar 

  • Charette S. J., Lavoie J. N., Lambert H., and Landry J. (2000) Inhibition of DAXX-mediated apoptosis by heat shock protein 27. Mol. Cell. Biol. 20, 7602–7612.

    Article  PubMed  CAS  Google Scholar 

  • Chen H. K., Fernandez-Funez P., Acevedo S. F., Lam Y. C., Kaytor M. D., Fernandez M. H., et al. (2003) Interaction of Akt-phosphorylated ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1. Cell 113, 457–68.

    Article  PubMed  CAS  Google Scholar 

  • Chen S., Berthelier V., Hamilton J. B., O’Nuallain B., and Wetzel R. (2002) Amyloid-like features of polyglutamine aggregates and their assembly kinetics. Biochemistry 41, 7391–7399.

    Article  PubMed  CAS  Google Scholar 

  • Chen S., Berthelier V., Yang W., and Wetzel R. (2001) Polyglutamine aggregation behaviour in vitro supports a recruitment mechanism of cytotoxicity. J. Mol. Biol. 311, 173–182.

    Article  PubMed  CAS  Google Scholar 

  • Chernoff Y. O., Lindquist S. L., Ono B., Inge-Vechtomov S. G., and Liebman S. W. (1995) Role of the chaperone protein Hsp104 in propagation of the yeast prion-like factor [psi+]. Science 268, 880–884.

    Article  PubMed  CAS  Google Scholar 

  • Clark J. I. and Muchowski P. J. (2000) Small heat-shock proteins and their potential role in human disease. Curr. Opin. Struct. Biol. 10, 52–59.

    Article  PubMed  CAS  Google Scholar 

  • Clarke G., Collins R. A., Leavitt B. R., Andrews D. F., Hayden M. R., Lumsden C. J., and McInnes R. R. (2000) A one-hit model of cell death in inherited neuronal degenerations. Nature 406, 195–199.

    Article  PubMed  CAS  Google Scholar 

  • Connell P., Ballinger C. A., Jiang J., Wu Y., Thompson L. J., Hohfeld J., Patterson C., et al. (2001) The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins. Nat. Cell. Biol. 3, 93–96.

    Article  PubMed  CAS  Google Scholar 

  • Coux O., Tanaka K., and Goldberg A. L. (1996) Structure and function of the 20S and 26S proteasomes. Annu. Rev. Biochem. 65, 801–847.

    Article  PubMed  CAS  Google Scholar 

  • Cowan K. J., Diamond M. I., and Welch W. J. (2003) Polyglutamine protein aggregation and toxicity are linked to cellular stress response. Hum. Mol. Genet. 12, 1377–1391.

    Article  PubMed  CAS  Google Scholar 

  • Cuervo A. M. and Dice J. F. (2000) Age-related decline in chaperone-mediated autophagy. J. Biol. Chem. 275, 31505–31513.

    Article  PubMed  CAS  Google Scholar 

  • Cummings C. J. and Zoghbi H. Y. (2000a) Fourteen and counting: unraveling trinucleotide repeat diseases. Hum Mol Genet. 9, 909–916.

    Article  PubMed  CAS  Google Scholar 

  • Cummings C. J. and Zoghbi H. Y. (2000b) Trinucleotide repeats: mechanisms and pathophysiology. Annu. Rev. Genomics Hum. Genet. 1, 281–328.

    Article  PubMed  CAS  Google Scholar 

  • Cummings C. J., Mancini M. A., Antalffy B., DeFranco D. B., Orr H. T., and Zoghbi H. Y. (1998) Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1. Nat. Genet. 19, 148–154.

    Article  PubMed  CAS  Google Scholar 

  • Cummings C. J., Reinstein E., Sun Y., Antalffy B., Jiang Y., Ciechanover A., et al. (1999) Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice. Neuron 24, 879–892.

    Article  PubMed  CAS  Google Scholar 

  • Cummings C. J., Sun Y., Opal P., Antalffy B., Mestril R., Orr H. T., et al. (2001) Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice. Hum. Mol. Genet. 10, 1511–1518.

    Article  PubMed  CAS  Google Scholar 

  • Deckel A. W. (2001) Nitric oxide and nitric oxide synthase in Huntington’s disease. J. Neurosci. Res. 64, 99–107.

    Article  PubMed  CAS  Google Scholar 

  • Demand J., Alberti S., Patterson C., and Hahfeld J. (2001) Cooperation of a ubiquitin domain protein and an E3 ubiquitin ligase during chaperone/proteasome coupling. Curr. Biol. 11, 1569–1577.

    Article  PubMed  CAS  Google Scholar 

  • DiFiglia M., Sapp E., Chase K. O., Davies S. W., Bates G. P., Vonsattel J. P., and Aronin N. (1997) Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277, 1990–1993.

    Article  PubMed  CAS  Google Scholar 

  • Donaldson K. M., Li W., Ching K. A., Batalov S., Tsai C. C., and Joazeiro C. A. (2003) Ubiquitin-mediated sequestration of normal cellular proteins into polyglutamine aggregates. Proc. Natl. Acad. Sci. USA 100(15), 8892–8897.

    Article  PubMed  CAS  Google Scholar 

  • Doss-Pepe E. W., Stenroos E. S., Johnson W. G., and Madura K. (2003) Ataxin-3 interactions with rad23 and valosin-containing protein and its associations with ubiquitin chains and the proteasome are consistent with a role in ubiquitin-mediated proteolysis. Mol. Cell. Biol. 23(18), 6469–6483.

    Article  PubMed  CAS  Google Scholar 

  • Dunah A. W., Jeong H., Griffin A., Kim Y. M., Standaert D. G., Hersch S. M., et al., (2002) Sp1 and TAFII130 transcriptional activity disrupted in early Huntington’s disease. Science 296, 2238–2243.

    Article  PubMed  CAS  Google Scholar 

  • Eaton P., Fuller W., and Shattock M. J. (2002) S-thiolation of HSP27 regulates its multimeric aggregate size independently of phosphorylation. J. Biol. Chem. 277, 21189–21196.

    Article  PubMed  CAS  Google Scholar 

  • Emamian E. S., Kaytor M. D., Duvick L. A., Zu T., Tousey S. K., Zoghbi H. Y., et al. (2003) Serine 776 of ataxin-1 is critical for polyglutamine-induced disease in SCA1 transgenic mice. Neuron 38, 375–387.

    Article  PubMed  CAS  Google Scholar 

  • Evert B.O., Vogt I. R., Vieira-Saecker A. M., Ozimek L., de Vos R. A., Brunt E. R., et al. (2003) Gene expression profiling in ataxin-3 expressing cell lines reveals distinct effects of normal and mutant ataxin-3. J. Neuropathol. Exp. Neurol. 62, 1006–1018.

    PubMed  CAS  Google Scholar 

  • Fernandez-Funez P., Nino-Rosales M. L., de Gouyon B., She W. C., Luchak J. M., Martinez P., et al. (2000) Identification of genes that modify ataxin-1-induced neurodegeneration. Nature 408, 101–106.

    Article  PubMed  CAS  Google Scholar 

  • Ferrante R. J., Andreassen O. A., Dedeglu A., Ferrante K. L., Jenkins B. G., Hersch S. M., and Beal M. F. (2002) Therurapeutic effects of coenzyme Q10 and Remacemide in transgenic mouse models of Huntington’s disease. J. Neurosci. 22, 1592–1599.

    PubMed  CAS  Google Scholar 

  • Fleury C., Mignotte B., and Vayssiere J. L. (2002) Mitochondrial oxygen species in cell death signaling. Biochimie 84, 131–141.

    Article  PubMed  CAS  Google Scholar 

  • Gabai V. L., Meriin A. B., Yaglom J. A., Wei J. Y., Mosser D. D., and Sherman M. Y., (2000a) Suppression of stress kinase JNK is involved in HSP72-mediated protection of myogenic cells from transient energy deprivation. HSP72 alleviates the stress-induced inhibition of JNK dephosphorylation. J. Biol. Chem. 275, 38088–38094.

    Article  PubMed  CAS  Google Scholar 

  • Gabai V. L., Yaglom J. A., Volloch V., Meriin A. B., Force T., Koutroumanis M., et al. (2000b) Hsp70-mediated suppression of c-Jun N-terminal kinase is implicated in development of tolerance to caspase-independent cell death. Mol. Cell. Biol. 20, 6826–6836.

    Article  PubMed  CAS  Google Scholar 

  • Garcia-Mata R., Bebok Z., Sorscher E. J., and Sztul E. S. (1999) Characterization and dynamics of aggresome formation by a cytosolic GFP-chimera. J. Cell. Biol. 146, 1239–1254.

    Article  PubMed  CAS  Google Scholar 

  • Garrido C., Bruey J. M., Fromentin A., Hammann A., Arrigo A. P., and Solary E. (1999) HSP27 inhibits cytochrome c-dependent activation of procaspase-9. FASEB J. 13, 2061–2070.

    PubMed  CAS  Google Scholar 

  • Gervais F. G., Singaraja R., Xanthoudakis S., Gutekunst C. A., Leavitt B. R., Metzler M., et al. (2002) Recruitment and activation of caspase-8 by the huntingtin-interacting protein Hip-1 and a novel partner Hippi. Nat. Cell. Biol. 4, 95–105.

    Article  PubMed  CAS  Google Scholar 

  • Giuliano P., De Cristofaro T., Affaitati A., Pizzulo G. M., Feliciello A., Criscuolo C., et al. (2003) DNA damage induced by polyglutamine-expanded proteins. Hum. Mol. Genet. 12, 2301–2309.

    Article  PubMed  CAS  Google Scholar 

  • Green D. R. (1998) Apoptotic pathways: the roads to ruin. Cell 94, 695–698.

    Article  PubMed  CAS  Google Scholar 

  • Green G. R. (1999) Harm’s way: polyglutamine repeats and the activation of an apoptotic pathway. Neuron 22, 416–417.

    Article  PubMed  CAS  Google Scholar 

  • Guidetti P., Charles V., Chen E. Y., Reddy P. H., Kordower J. H., Whetsell W. O., Jr., et al. (2001) Early degenerative changes in transgenic mice expressing mutant huntingtin involve dendritic abnormalities but no impairment of mitochondrial energy production. Exp. Neurol. 169, 340–350.

    Article  PubMed  CAS  Google Scholar 

  • Gunawardena S., Her L. S., Brusch R. G., Laymon R. A., Niesman I. R., Gordesky-Gold B., et al. (2003) Disruption of axonal transport by loss of huntingtin or expression of pathogenic polyQ proteins in Drosophila. Neuron 40, 25–40.

    Article  PubMed  CAS  Google Scholar 

  • Gurbuxani S., Schmitt E., Cande C., Parcellier A., Hammann A., Daugas E., et al. (2003) Heat shock protein 70 binding inhibits the nuclear import of apoptosis-inducing factor. Oncogene 22, 6669–6678.

    Article  PubMed  CAS  Google Scholar 

  • Gusella J. F. and McDonald M. E. (2000) Molecular genetics: unmasking polyglutamine triggers in neurodegenerative disease. Nat. Rev. Neurosci. 1, 109–115.

    Article  PubMed  CAS  Google Scholar 

  • Gutekunst C. A., Li S. H., Yi H., Ferrante R. J., Li X. J., and Hersch S. M. (1998) The cellular and subcellular localisation of huntingtin-associated protein 1 (HAP-1): comparison with huntingtin in rat and human. J. Neurosci. 18, 7674–7686.

    PubMed  CAS  Google Scholar 

  • Hansson O., Nylandsted J., Castilho R. F., Leist M., Jaattela M., and Brundin P. (2003) Overexpress on of heat shock protein 70 in R6/2 Huntington’s disease mice has only modest effects on disease progression. Brain Res. 970, 47–57.

    Article  PubMed  CAS  Google Scholar 

  • Harper S. J. and LoGrasso P. (2001) Signalling for survival and death in neurones: the role of stress-activated kinases, JNK and p38. Cell Signal. 13, 299–310.

    Article  PubMed  CAS  Google Scholar 

  • Hartl F. U. (1996) Molecular chaperones in cellular protein folding. Nature 381, 571–579.

    Article  PubMed  CAS  Google Scholar 

  • Hartl F. U. and Hayer-Hartl M. (2002) Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 295, 1852–1858.

    Article  PubMed  CAS  Google Scholar 

  • Higashiyama H., Hirose F., Yamaguchi M., Inoue Y. H., Fujikake N., Matsukage A., and Kakizuka A. (2002) Identification of ter94, Drosophila VCP, as a modulator of polyglutamine-induced neurodegeneration. Cell Death Differ. 9, 264–273.

    Article  PubMed  CAS  Google Scholar 

  • Hochstrasser M. (1996) Ubiquitin-dependent protein degradation. Annu. Rev. Genet. 30, 405–439.

    Article  PubMed  CAS  Google Scholar 

  • Holbert S., Denghien I., Kiechle T., Rosenblatt A., Wellington C., et al. (2001)

  • The Gln-Ala repeat transcriptional activator CA 150 interacts with huntingtin: neuropathologic and genetic evidence for a role in Huntington’s disease pathogenesis. Proc. Natl. Acad. Sci. USA 98, 1811–1816.

  • Hsu A. L., Murphy C. T., and Kenyon C. (2003) Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science 300, 1142–1145.

    Article  PubMed  CAS  Google Scholar 

  • Humbert S., Bryson E. A., Cordelieres F. P., Connors N. C., Datta S. R., Finkbeiner S., et al. (2002) The IGF-1/Akt pathway is neuroprotective in Huntington’s disease and involves Huntingtin phosphorylation by Akt. Dev. Cell 2, 831–837.

    Article  PubMed  CAS  Google Scholar 

  • Ishihara K., Yamagishi N., Saito Y., Adachi H., Kobayashi Y., Sobue G., et al. (2003) Hsp105α suppresses the aggregation of truncated androgen receptor with expanded CAG repeats and cell toxicity. J. Biol. Chem. 278, 25143–25150.

    Article  PubMed  CAS  Google Scholar 

  • Jackson G. R., Salecker I., Dong X., Yao X., Arnheim N., Faber P. W., et al. (1998) Polyglutamine-expanded human huntingtin transgenes induce degeneration of Drosophila photoreceptor neurons. Neuron 21, 633–642.

    Article  PubMed  CAS  Google Scholar 

  • Jana N. R., Tanaka M., Wang G. H., and Nukina N. (2000) Polyglutamine length dependent interaction of Hsp40 and HSP70 family chaperones with truncated N-terminal huntingtin: their suppression of aggregation and cellular toxicity Hum. Mol. Genet. 9, 2009–2018.

    Article  PubMed  CAS  Google Scholar 

  • Jana N. R., Zemskov E. A., Wang G. H., and Nukina N. (2001) Altered proteasomal function due to the expression of polyglutamine-expanded truncated N-terminal huntingtin induces apoptosis by caspase activation through mitochondrial cytochrome crelease. Hum. Mol. Genet. 10, 1049–1059.

    Article  PubMed  CAS  Google Scholar 

  • Johnston J. A., Ward C. L., and Kopito R. R. (1998) Aggresomes: a cellular response to misfolded proteins. J. Cell. Biol. 143, 1883–1898.

    Article  PubMed  CAS  Google Scholar 

  • Jolly C. and Morimoto R. I. (2000) Role of the heat shock response and molecular chaperones in oncogenesis and cell death. J. Natl. Cancer Inst. 92, 1564–1572.

    Article  PubMed  CAS  Google Scholar 

  • Jones L. (1999) The localisation and interactions of huntingtin. Philos. Trans. R Soc. Lond. B Biol. Sci. 354, 1021–1027.

    Article  PubMed  CAS  Google Scholar 

  • Kaplan D. R. and Miller F. D. (2000) Neurotrophin signal transduction in the nervous system. Curr. Opin. Neurobiol. 10, 381–391.

    Article  PubMed  CAS  Google Scholar 

  • Kato H., Liu Y., Kogure K., and Kato K. (1994) Induction of 27 kDa heat shock protein following cerebral ischemia in a rat model of ischemic tolerance. Brain Res. 634, 235–244.

    Article  PubMed  CAS  Google Scholar 

  • Kaytor M. D., Duvick L. A., Skinner P. J., Koob M. D., Ranum L. P., and Orr H. T. (1999) Nuclear localization of the spinocerebellar ataxia type 7 protein, ataxin-7. Hum. Mol. Genet. 8, 1657–1664.

    Article  PubMed  CAS  Google Scholar 

  • Kazantsev A., Preisinger E., Dranovsky A., Goldgaber D., and Housman D. (1999) Insoluble detergent-resistant aggregates form between pathological and nonpathological lengths of polyglutamine in mammalian cells. Proc. Natl. Acad. Sci. USA 96, 11404–11409.

    Article  PubMed  CAS  Google Scholar 

  • Kazemi-Esfarjani P. and Benzer S. (2000) Genetic suppression of polyglutamine toxicity in Drosophila. Science 287, 1837–1840.

    Article  PubMed  CAS  Google Scholar 

  • Kegel K. B., Kim M., Sapp E., McIntyre C., Castano J. G., Aronin N., and DiFiglia M. (2000) Huntingtin expression stimulates endosomal-lysosomal activity, endosome tubulation, and autophagy. J Neurosci. 20, 7268–7278.

    PubMed  CAS  Google Scholar 

  • Kiechle T., Dedeoglu A., Kubilus J., Kowall N. W., Beal M.F., Friedlander R., et al. (2002) Cytochrome c and caspase-9 expression in Huntington’s disease. Neuromol. Med. 1, 183–195.

    Article  CAS  Google Scholar 

  • Kim M., Lee H. S., LaForet G., McIntyre C., Martin E. J., Chang P., et al. (1999) Mutant huntingtin expression in clonal striatal cells: dissociation of inclusion formation and neuronal survival by caspase inhibition. J. Neurosci. 19, 964–973.

    PubMed  CAS  Google Scholar 

  • Kim S., Nollen E. A, Kitagawa K., Bindokas V. P., and Morimoto R. I. (2002) Polyglutamine protein aggregates are dynamic. Nat. Cell. Biol. 4, 826–831.

    Article  PubMed  CAS  Google Scholar 

  • Kisselev A. F., Akopian T. N., Woo K. M., and Goldberg A. L. (1999) The sizes of peptides generated from protein by mammalian 26 and 20S proeasomes. Implications for understanding the degradative mechanisms and antigen presentation. J. Biol. Chem. 274, 3363–3371.

    Article  PubMed  CAS  Google Scholar 

  • Kita H., Carmichael J., Swartz J., Muro S., Wyttenbach A., Matsubara K., et al. (2002) Modulation of polyglutamine-induced cell death by genes identified by expression profiling. Hum. Mol. Genet. 11, 2279–2287.

    Article  PubMed  CAS  Google Scholar 

  • Kobayashi Y., Kume A., Li M., Doyu M., Hata M., Ohtsuka K., and Sobue G. (2000) Chaperones Hsp70 and Hsp40 suppress aggregate formation and apoptosis in cultured neuronal cells expressing truncated androgen receptor protein with expanded polyglutamine tract. J. Biol. Chem. 275, 8772–8778.

    Article  PubMed  CAS  Google Scholar 

  • Konishi H., Matsuzaki H., Tanaka M., Takemura Y., Kuroda S., Ono Y., and Kikkawa U. (1997) Activation of protein kinase B (Akt/RAC-protein kinase) by cellular stress and its association with heat shock protein Hsp27. FEBS Lett. 410, 493–498.

    Article  PubMed  CAS  Google Scholar 

  • Kopito R. R. (2000) Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol. 10, 524–530.

    Article  PubMed  CAS  Google Scholar 

  • Kouroku Y., Fujita E., Jimbo A., Kikuchi T., Yamagata T., Momoi M. Y., et al. (2002) Polyglutamine aggregates stimulate ER stress signals and caspase-12 activation. Hum. Mol. Genet. 11, 1505–1515.

    Article  PubMed  CAS  Google Scholar 

  • Krobitsch S. and Lindquist S. (2000) Aggregation of huntingtin in yeast varies with the length of the polyglutamine expansion and the expression of chaperone proteins. Proc. Natl. Acad. Sci. USA 97, 1589–1594.

    Article  PubMed  CAS  Google Scholar 

  • La-Fevre-Bernt M. A. and Ellerby L. M. (2003) Kennedy’s disease. Phosphorylation of the polyglutamine-expanded form of androgen receptor regulates its cleavage by caspase-3 and enhances cell death. J. Biol. Chem. 278, 34918–34924.

    Article  CAS  Google Scholar 

  • Lemon B. and Tjian R. (2000) Orchestrated response: a symphony of transcription factors for gene control. Genes Dev. 14, 2551–2569.

    Article  PubMed  CAS  Google Scholar 

  • Li H., Yu Z. Z., Shelbourne P., and Li X. J. (2001) Huntingtin aggregate associated axonal degeneration is an early pathological event in Huntington’s disease. J. Neurosci. 21, 8473–8481.

    PubMed  CAS  Google Scholar 

  • Li H., Zhu H., Xu C. J., and Yuan J. (1998) Cleavage of BID by caspase-8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94, 491–501.

    Article  PubMed  CAS  Google Scholar 

  • Li L. Y., Luo X., and Wang X. (2001) Endonuclease G is an apoptotic Dnase when released from mitochondria. Nature 412, 95–99.

    Article  PubMed  CAS  Google Scholar 

  • Li S. H., Lam S., Cheng A. L, and Li X. J. (2000) Intranuclear huntingtin increases the expression of caspase-1 and induces apoptosis. Hum. Mol. Genet. 9, 2859–2867.

    Article  PubMed  CAS  Google Scholar 

  • Lieberman A. P., Harmison G., Strand A. D., Olson J. M., and Fischbeck K. H. (2002) Altered transcriptional regulation in cells expressing the expanded polyglutamine androgen receptor. Hum. Mol. Genet. 11, 1967–1976.

    Article  PubMed  CAS  Google Scholar 

  • Lin X., Antalffy B., Kang D., Orr H. T., and Zoghbi H. Y. (2000) Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1. Nat. Neurosci. 3, 157–163.

    Article  PubMed  CAS  Google Scholar 

  • Liu Y. F. (1998) Expression of polyglutamine-expanded Huntingtin activates the SEK1-JNK pathway and induces apoptosis in a hippocampal neuronal cell line. J. Biol. Chem. 273(44), 28873–28877.

    Article  PubMed  CAS  Google Scholar 

  • Liu Y. F., Dorow D., and Marshall J. (2000) Activation of MLK2-mediated signaling cascades by polyglutamine-expanded huntingtin. J. Biol. Chem. 275, 19035–19040.

    Article  PubMed  CAS  Google Scholar 

  • Lockshin R. A. and Zakeri Z. (2002) Caspase-independent cell deaths. Curr. Opin. Cell. Biol. 14, 727–733.

    Article  PubMed  CAS  Google Scholar 

  • Lonze B. E. and Ginty D. D. (2002) Function and regulation of CREB family transcription factors in the nervous system. Neuron 35, 605–623.

    Article  PubMed  CAS  Google Scholar 

  • Ludwig S., Engel K., Hoffmeyer A., Sithanandam G., Neufeld B., Palm D., et al. (1996) 3pK, a novel mitogenactivated protein (MAP) kinase-activated protein kinase, is targeted by three MAP-kinase pathways. Mol. Cell. Biol. 16, 6687–6697.

    PubMed  CAS  Google Scholar 

  • Luthi-Carter R., Hanson S. A., Strand A. D., Bergstrom D. A., Chun W., Peters N. L., et al. (2002a) Dysregulation of gene expression in the R6/2 model of polyglutamine disease: parallel changes in muscle and brain. Hum. Mol. Genet. 11, 1911–1926.

    Article  PubMed  CAS  Google Scholar 

  • Luthi-Carter R., Strand A. D., Hanson S. A., Kooperberg C., Schilling G., La Spada A. R., et al. (2002b) Polyglutamine and transcription: gene expression changes shared by DRPLA and Huntington’s disease mouse models reveal context-independent effects. Hum. Mol. Genet. 11, 1927–1937.

    Article  PubMed  CAS  Google Scholar 

  • Luthi-Carter R., Strand A., Peters N. L., Solano S. M., Hollingsworth Z. R., Menon A. S., et al. (2000) Decreased expression of striatal signaling genes in a mouse model of Huntington’s disease. Hum. Mol. Genet. 9, 1259–1271.

    Article  PubMed  CAS  Google Scholar 

  • Martinou J. C. and Green D. R. (2001) Breaking the mitochondrial barrier. Nat. Rev. Cell. Biol. 2, 63–67.

    Article  CAS  Google Scholar 

  • Mattson M. P., Chan S. L., and Duan W. (2002) Modification of brain aging and neurodegenerative disorders by genes, diet and behavior. Physiol. Rev. 82, 637–672.

    PubMed  CAS  Google Scholar 

  • McCampbell A., Taylor J. P., Taye A. A., Robitschek J., Li M., Walcott J., et al. (2000) CREB-binding protein sequestration by expanded polyglutamine. Hum. Mol. Genet. 9, 2197–2202.

    Article  PubMed  CAS  Google Scholar 

  • Mearow K. M., Dodge M. E., Rahimtula M., and Yegappan C. (2002) Stress-mediated signaling in PC12 cells—the role of the small heat shock protein, Hsp27, and Akt in protecting cells from heat stress and nerve growth factor withdrawal. J. Neurochem. 83, 452–462.

    Article  PubMed  CAS  Google Scholar 

  • Mehlen P., Hickey E., Weber L. A., and Arrigo A. P. (1997) Large unphosphorylated aggregates as the active form of hsp27 which controls intracellular reactive oxygen species and glutathione levels and generates a protection against TNFα in NIH-3T3-ras cells. Biochem. Biophys. Res. Commun. 241, 187–192.

    Article  PubMed  CAS  Google Scholar 

  • Merienne K., Helmlinger D., Perkin G. R., Devys D., and Trottier Y. (2003) Polyglutamine expansion induces a protein-damaging stress connecting heat shock protein 70 to the JNK pathway. J. Biol Chem. 278, 16957–16967.

    Article  PubMed  CAS  Google Scholar 

  • Meriin A. B., Yaglom J. A., Gabai V. L., Zon L., Ganiatsas S., Mosser D. D., et al. (1999) Protein-damaging stresses activate c-Jun N-terminal kinase via inhibition of its dephosphorylation: a novel pathway controlled by HSP72. Mol. Cell. Biol. 19, 2547–2555.

    PubMed  CAS  Google Scholar 

  • Mitsui K., Nakayama H., Akagi T., Nekooki M., Ohyawa K., Takio K., et al. (2002) Purification of polyglutamine aggregates and identification of elongation factor-1a and heat shock protein 84 as aggregate-interacting proteins. J. Neurosci. 22, 9267–9277.

    PubMed  CAS  Google Scholar 

  • Miyashita T., Ohtsuka Y., Okamura-Oho Y., Shikama Y., and Yamada M. (2001) Extended polyglutamine selectively interacts with caspase-8 and -10 in nuclear aggregates. Cell Death Differ. 8, 377–386.

    Article  PubMed  CAS  Google Scholar 

  • Morimoto R. I. (2002) Dynamic remodeling of transcription complexes by molecular chaperones. Cell 110, 281–284.

    Article  PubMed  CAS  Google Scholar 

  • Morimoto R. I., Kline M. P., Bimston D. N., and Cotto J. J. (1997) The heat-shock response: regulation and function of heat-shock proteins and molecular chaperones. Essays Biochem. 32, 17–29.

    PubMed  CAS  Google Scholar 

  • Mosser D. D., Caron A. W., Bourget L., Meriin A. B., Sherman M. Y., Morimoto R. I., and Massie B. (2000) The chaperone function of hsp70 is required for protection against stress-induced apoptosis. Mol. Cell. Biol. 20, 7146–7159.

    Article  PubMed  CAS  Google Scholar 

  • Moulder K. L., Onodera O. Burke J. R., Strittmatter W. J., and Johnson, E. M., Jr. (1999) Generation of neuronal intranuclear inclusions by polyglutamine-GFP: analysis of inclusion clearance and toxicity as a function of polyglutamine length. J. Neurosci. 19, 705–715.

    PubMed  CAS  Google Scholar 

  • Muchowski P. J., Ning K., D’Souza-Schorey C., and Fields S. (2002) Requirement of an intact microtubule cytoskeleton for aggregation and inclusion body formation by a mutant huntingtin fragment. Proc. Natl. Acad. Sci. USA 99, 727–732.

    Article  PubMed  CAS  Google Scholar 

  • Muchowski P.J., Schaffar G., Sittler A., Wanker E. E., Hayer-Hartl M. K., and Hartl F. U. (2000) Hsp70 and hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils. Proc. Natl. Acad. Sci. USA 97, 7841–7846.

    Article  PubMed  CAS  Google Scholar 

  • Muzio M., Chinnaiyan A. M., Kischkel F. C., O’Rourke K., Shevchenko A., Ni J., et al. (1996) FLICE, a novel FADD-homologous ICE/CED-3 like protease, is recruited to the CD95 (Fas/Apo-1) death-inducing signaling complex. Cell 85, 817–827.

    Article  PubMed  CAS  Google Scholar 

  • Narain Y., Wyttenbach A., Rankin J., Furlong R. A., and Rubinzstein D. C. (1999) A molecular investigation of true dominance in Huntington’s disease. J. Med. Genet. 36, 739–746.

    PubMed  CAS  Google Scholar 

  • Nishitoh H., Matsuzawa A., Tobiume K., Saegusa K., Takeda K., Inoue K., et al. (2002) ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev. 16, 1345–1355.

    Article  PubMed  CAS  Google Scholar 

  • Nucifora F. C., Jr., Sasaki M., Peters M.F., Huang H., Cooper J. K., Yamada M., et al. (2001) Interference by huntingtin and atrophin-1 with cbp-mediated transcription leading to cellular toxicity. Science 291, 2423–2428.

    Article  PubMed  CAS  Google Scholar 

  • Opal P. and Zoghbi H. Y. (2002) The role of chaperones in polyglutamine disease. Trends Mol. Med. 8, 232–236.

    Article  PubMed  CAS  Google Scholar 

  • Pandey P., Farber R., Nakazawa A., Kumar S., Bharti A., Nalin C., et al. (2000a) Hsp27 functions as a negative regulator of cytochrome c-dependent activation of procaspase-3. Oncogene 19, 1975–1981.

    Article  PubMed  CAS  Google Scholar 

  • Pandey P., Saleh A., Nakazawa A., Kumar S., Srinivasula S. M., Kumar V., et al. (2000b) Negative regulation of cytochrome c-mediated oligomerization of Apaf-1 and activation of procaspase-9 by heat shock protein 90. EMBO J. 19, 4310–4322.

    Article  PubMed  CAS  Google Scholar 

  • Parcellier A., Schmitt E., Gurbuxani S., Seigneurin-Berny D., Pance A., Chantome A., et al. (2003) HSP27 is a ubiquitin-binding protein involved in IκBα proteasomal degradation. Mol. Cell. Biol. 23, 5790–5802.

    Article  PubMed  CAS  Google Scholar 

  • Park H. S., Cho S. G., Kim C. K., Hwang H. S., Noh K. T., Kim M. S., et al. (2002) Heat shock protein hsp72 is a negativeregulator of apoptosis signal-regulating kinase 1. Mol. Cell. Biol. 22(22), 7721–7730.

    Article  PubMed  CAS  Google Scholar 

  • Park H. S., Lee J. S., Huh S. H., Seo J. S., and Choi E. J. (2001) Hsp72 functions as a natural inhibitory protein of c-Jun N-terminal kinase. EMBO J. 20, 446–456.

    Article  PubMed  CAS  Google Scholar 

  • Patino M. M., Liu J. J., Glover J. R., and Lindquist S. (1996) Support for the prion hypothesis for inheritance of a phenotypic trait in yeast. Science 273, 622–626.

    Article  PubMed  CAS  Google Scholar 

  • Paulson H. L., Bonini N. M., and Roth K. A. (2000) Polyglutamine disease and neuronal cell death. Proc. Natl. Acad. Sci. USA 97, 12957,12958.

    Article  PubMed  CAS  Google Scholar 

  • Perez M. K., Paulson H. L., Pendse S. J., Saionz S. J., Bonini N. M., and Pittman R. N. (1998) Recruitment and the role of nuclear localisation in polyglutamine-mediated aggregation. J. Cell Biol. 143, 1457–1470.

    Article  PubMed  CAS  Google Scholar 

  • Perutz M. F. (1999) Glutamine repeats and neurodegenerative diseases: molecular aspects. Trends Biochem. Sci. 24, 58–63.

    Article  PubMed  CAS  Google Scholar 

  • Perutz M. F. and Windle A. H. (2001) Cause of neural death in neurodegenerative diseases attributable to expansions of glutamine repeats. Nature 412, 143–144.

    Article  PubMed  CAS  Google Scholar 

  • Perutz M. F., Johnson T., Suzuki M., and Finch J. T. (1994) Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases. Proc. Natl. Acad. Sci. USA 91, 5355–5358.

    Article  PubMed  CAS  Google Scholar 

  • Perutz M. F., Pope B. J., Owen D., Wanker E. E., and Scherzinger E. (2002) Aggregation of proteins with expanded glutamine and alanine repeats of the glutamine-rich and asparagine-rich domains of Sup35 and of the amyloid beta-peptide of amyloid plaques. Proc. Natl. Acad. Sci. USA 99, 5596–5600.

    Article  PubMed  CAS  Google Scholar 

  • Portera-Cailliau C., Hedreen J. C., Price D. L., and Koliatsos V. E. (1995) Evidence for apoptotic cell death in Huntington disease and excitotoxic animal models. J. Neurosci. 15, 3775–3787.

    PubMed  CAS  Google Scholar 

  • Preisinger E., Jordan B. M., Kazantsev A., and Housman D. (1999) Evidence for a recruitment and sequestration mechanism in Huntington’s disease. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 354, 1029–1034.

    Article  PubMed  CAS  Google Scholar 

  • Rane M. J., Pan Y., Singh S., Powell D. W., Wu R., Cummins T., et al. (2003) Heat shock protein 27 controls apoptosis by regulating Akt activation. J. Biol. Chem. 278, 27828–27835.

    Article  PubMed  CAS  Google Scholar 

  • Ravagnan L., Gurbuxani S., Susin S. A., Maisse C., Daugas E., Zamzami N., et al. (2001) Heat-shock protein 70 antagonizes apoptosis-inducing factor. Nat. Cell. Biol. 3, 839–843.

    Article  PubMed  CAS  Google Scholar 

  • Ravikumar B., Duden R., and Rubinsztein D. C. (2002) Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum. Mol. Genet. 11, 1107–1117.

    Article  PubMed  CAS  Google Scholar 

  • Ravikumar B. Stewart A., Kita H., Kato K., Duden R., and Rubinsztein D. C. (2003) Raised intracellular glucose concentrations reduce aggregation and cell death caused by mutant huntingtin exon 1 by decreasing mTOR phosphorylation and inducing autophagy. Hum. Mol. Genet. 12, 985–994.

    Article  PubMed  CAS  Google Scholar 

  • Reddy P. H., Williams M., Charles V., Garret L., Pike-Buchanan L., Whetsell W. O., et al. (1998) Behavioural abnormalities and selective neuronal loss in HD transgenic mice expressing mutated full-length HD cDNA. Nat. Genet. 20, 198–202.

    Article  PubMed  CAS  Google Scholar 

  • Reggiori F. and Klionsky D. J. (2002) Autophagy in the eukaryotic cell. Eukaryot. Cell 1, 11–21.

    Article  PubMed  CAS  Google Scholar 

  • Rigamonti D., Bauer J. H., De-Fraja C., Conti L., Sipione S., Sciorati C., et al. (2000) Wild-type huntingtin protects from apoptosis upstream of caspase-3. J Neurosci. 20, 3705–3713.

    PubMed  CAS  Google Scholar 

  • Rochet J. C. and Lansbury P. T., Jr. (2000) Amyloid fibrillogenesis: themes and variations. Curr. Opin. Struct. Biol. 10, 60–68.

    Article  PubMed  CAS  Google Scholar 

  • Rock K. L., Gramm C., Rothstein L., Clark K., Stein R., Dick L., et al. (1994) Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules. Cell 78, 761–771.

    Article  PubMed  CAS  Google Scholar 

  • Rogalla T., Ehrnsperger M., Preville X., Kotlyarov A., Lutsch G., Ducasse C., et al. (1999) Regulation of Hsp27 oligomerization, chaperone function, and protective activity against oxidative stress/tumor necrosis factor alpha by phosphorylation. J. Biol. Chem. 274, 18947–18956.

    Article  PubMed  CAS  Google Scholar 

  • Ross C. A. (1995) When more is less: pathogenesis of glutamine repeat neurodegenerative diseases. Neuron 15, 493–496.

    Article  PubMed  CAS  Google Scholar 

  • Ross C. A. (2002) Polyglutamine pathogenesis: emergence of unifying mechanisms for Huntington’s disease and related disorders. Neuron 35, 819–822.

    Article  PubMed  CAS  Google Scholar 

  • Ross C. A., Poirier M. A., Wanker E. E., and Amzel M. (2003) Polyglutamine fibrillogenesis: the pathway unfolds. Proc. Natl. Acad. Sci. USA 100, 1–3.

    Article  PubMed  CAS  Google Scholar 

  • Rubinsztein D. C. and Hayden M. R. (1998) Analysis of Triplet Disorders. BiosScientific Publishers, Oxford, UK, p. 327.

    Google Scholar 

  • Sakahira H., Breuer P., Hayer-Hartl M. K., and Hartl F. U. (2002) Molecular chaperones as modulators of polyglutamine protein aggregation and toxicity. Proc. Natl. Acad. Sci. USA 99(Suppl. 4), 16412–16418.

    Article  PubMed  CAS  Google Scholar 

  • Saleh A., Srinivasula S. M., Balkir L., Robbins P. D., and Alnemri E. S. (2000) Negative regulation of the Apaf-1 apoptosome by Hsp70. Natl. Cell Biol. 2, 476–483.

    Article  CAS  Google Scholar 

  • Sanchez I., Xu C. J., Juo P., Kakizaka A., Blenis J., and Yuan J. (1999) Caspase-8 is required for cell death induced by expanded polyglutamine repeats. Neuron 22, 623–633.

    Article  PubMed  CAS  Google Scholar 

  • Sapp E., Schwarz C., Chase K., Bhide P. G., Young A. B., et al. (1997) Huntingtin localization in brains of normal and Huntington’s disease patients. Ann. Neurol. 42, 604–612.

    Article  PubMed  CAS  Google Scholar 

  • Sato S., Fujita N., and Tsuruo T. (2000) Modulation of Akt kinase activity by binding to Hsp90. Proc. Natl. Acad. Sci. USA 97, 10832–10837.

    Article  PubMed  CAS  Google Scholar 

  • Satyal S. H., Schmidt E., Kitagawa K., Sondheimer N., Lindquist S., Kramer J. M., and Morimoto R. I. (2000) Polyglutamine aggregates alter protein folding homeostasis in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 97, 5750–5755.

    Article  PubMed  CAS  Google Scholar 

  • Saudou F., Finkbeiner S., Devys D., and Greenberg M. E. (1998) Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95, 55–66.

    Article  PubMed  CAS  Google Scholar 

  • Scherzinger E., Lurz R., Turmaine M., Mangiarini L., Hollenbach B., et al. (1997)

  • Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo. Cell 90, 549–558.

  • Scherzinger E., Sittler A., Schweiger K., Heiser V., Lurz R., Hasenbank R., et al. (1999) Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: implications for Huntington’s disease pathology. Proc. Natl. Acad. Sci. USA 96, 4604–4609.

    Article  PubMed  CAS  Google Scholar 

  • Sherman M. Y. and Goldberg A. L. (2001) Cellular defenses against unfolded proteins: a cell biologist thinks about neurodegenerative diseases. Neuron 29, 15–32.

    Article  PubMed  CAS  Google Scholar 

  • Shimohata T., Nakajima T., Yamada M., Uchida C., Onodera O., Naruse S., et al. (2000) Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription. Nat. Genet. 26, 29–36.

    Article  PubMed  CAS  Google Scholar 

  • Sipione S., Rigamonti D., Valenza M., Zuccato C., Conti L., Pritchard J., et al. (2002) Early transcriptional profiles in huntingtin-inducible striatal cells by microarray analyses. Hum. Mol. Genet. 11, 1953–1965.

    Article  PubMed  CAS  Google Scholar 

  • Sittler A., Lurz R., Lueder, G., Priller J., Lehrach H., Hayer-Hartl M. K., et al. (2000) Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington’s disease. Hum. Mol. Genet. 10, 1307–1315.

    Article  Google Scholar 

  • Skinner P. J. Koshy B. T., Cummings C. J., Klement I. A., Helin K., Servadio A., et al. (1997) Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures. Nature 389, 971–978.

    Article  PubMed  CAS  Google Scholar 

  • Song Y., Cardounel A. J., Zweier J. L., and Xia Y. (2002) Inhibition of superoxide generation from neuronal nitric oxide synthase by heat shock protein 90: implications in NOS regulation. Biochemistry 41, 10616–10622.

    Article  PubMed  CAS  Google Scholar 

  • Soti C. and Csermely P. (2002) Chaperones and aging: role in neurodegeneration and in other civilizational diseases. Neurochem. Int. 41, 383–389.

    Article  PubMed  CAS  Google Scholar 

  • Steffan J. S., Bodai L., Pallos J., Poelman M., McCampbell A., et al. (2001) Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413, 739–743.

    Article  PubMed  CAS  Google Scholar 

  • Steffan J. S., Kazantsev A., Spasic-Boskovic O., Greenwald M., Zhu Y. Z., Gohler H., et al. (2000) The Huntington’s disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc. Natl. Acad. Sci. USA 97, 6763–6768.

    Article  PubMed  CAS  Google Scholar 

  • Stenoien D. L., Cummings C. J., Adams H. P., Mancini M. G., Patel K., DeMartino G. N., et al. (1999) Polyglutamine-expanded androgen receptors form aggregates that sequester heat shock proteins, proteasome components and SRC-1, and are suppressed by the HDJ-2 chaperone. Hum. Mol. Genet. 8, 731–741.

    Article  PubMed  CAS  Google Scholar 

  • Stenoien D. L., Mielke M., and Mancini M. A. (2002) Intranuclear ataxin1 inclusions contain both fast- and slow-exchanging components. Nat. Cell. Biol. 4, 806–810.

    Article  PubMed  CAS  Google Scholar 

  • Stokoe D., Engel K., Campbell D. G., Cohen P., and Gaestel M. (1992) Identification of MAPAKAP kinase 2 as a major enzyme responsible for the phosphorylation of small mammalian heat shock proteins. FEBS Lett. 313, 307–313.

    Article  PubMed  CAS  Google Scholar 

  • Suhr S. T., Senut M. C., Whitelegge J. P., Faull K. F., Cuizon D. B., and Gage F. H. (2001) Identities of sequestered proteins in aggregates from cells with induced polyglutamine expression. J. Cell. Biol. 153, 283–294.

    Article  PubMed  CAS  Google Scholar 

  • Susin S. A., Lorenzo N., Zamzami I., Marzo B. E., Snow G. M., Brothers J., et al. (1999) Molecular characterisation of mitochondrial apoptosis-inducing factor. Nature 397, 441–446.

    Article  PubMed  CAS  Google Scholar 

  • Szebenyi G., Morfini G. A., Babcock A., Gould M., Selkoe K., Stenoien D. L., et al. (2003) Neuropathogenic forms of huntingtin and androgen receptor inhibit fast axonal transport. Neuron 40, 41–52.

    Article  PubMed  CAS  Google Scholar 

  • Tabrizi S. J., Workman J., Hart P. E., Mangiarini L., Mahal A., Bates G., et al. (2000) Mitochondrial dysfunction and free radical damage in the Huntington’s R6/2 transgenic mouse. Ann. Neurol. 47, 80–86.

    Article  PubMed  CAS  Google Scholar 

  • Tanaka M., Machida Y., Nishikawa Y., Akagi T., Hashikawa T., Fujisawa T., and Nukina N. J. (2003) Expansion of polyglutamine induces the formation of quasiaggregate in the early stage of protein fibrillization. J. Biol. Chem. 278, 34717–34724.

    Article  PubMed  CAS  Google Scholar 

  • Taylor J. P., Tanaka F., Robitschek J., Sandoval C. M., Taye A., Markovic-Plese S., and Fischbeck K. H. (2003) Aggresomes protect cells by enhancing the degradation of toxic polyglutamine-containing protein. Hum. Mol. Genet. 12, 749–757.

    Article  PubMed  CAS  Google Scholar 

  • Tobiume K., Matsuzawa A., Takahashi T., Nishitoh H., Morita K., Takeda K., et al. (2001) ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis. EMBO Rep. 2, 222–228.

    Article  PubMed  CAS  Google Scholar 

  • Toyoshima I., Sugawara M., Kato K., Wada C., Shimohata T., Koide R., et al. (2002) Time course of polyglutamine aggregate body formation and cell death: enhanced growth in the nucleus and an interval for cell death. J. Neurosci. Res. 68, 442–448.

    Article  PubMed  CAS  Google Scholar 

  • Tsai Y. C., Fishman P. S., Thakor N. V., and Olyer G. A. (2003) Parkin facilitates the elimination of expanded polyglutamine proteins and leads to preservation of proteasome function. J. Biol. Chem. 278, 22044–22055.

    Article  PubMed  CAS  Google Scholar 

  • Turmaine M., Raza A., Mahal A., Mangiarini L., Bates G. P., and Davies S. W. (2000) Nonapoptotic neurodegeneration in a transgenic mouse model of Huntington’s disease. Proc. Natl. Acad. Sci. USA 97, 8093–8097.

    Article  PubMed  CAS  Google Scholar 

  • Verhoef L. G., Lindsten K., Masucci M. G., and Dantuma N. P. (2002) Aggregate formation inhibits proteasomal degradation of polyglutamine proteins. Hum. Mol. Genet. 11, 2689–2700.

    Article  PubMed  CAS  Google Scholar 

  • Vleminckx V., Van Damme P., Goffin K., Delye H., Van Den Bosch L., and Robberecht W. (2002) Upregulation of HSP27 in a transgenic model of ALS. J. Neuropathol. Exp. Neurol. 61, 968–974.

    PubMed  CAS  Google Scholar 

  • Waelter S., Boeddrich A., Lurz R., Scherzinger E., Lueder G., Lehrach H., and Wanker E. E. (2001) Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient degradation. Mol. Biol. Cell. 12, 1393–1407.

    PubMed  CAS  Google Scholar 

  • Wagstaff M. J., Collaco-Moraes Y., Smith J., de Belleroche J. S., Coffin R. S., and Latchman D. S. (1999) Protection of neuronal cells from apoptosis by Hsp27 delivered with a herpes simplex virus-based vector. J. Biol. Chem. 274, 5061–5069.

    Article  PubMed  CAS  Google Scholar 

  • Wanker E. E. (2000) Protein aggregation in Huntington’s disease and Parkinson’s disease: implications for pathology. Mol. Med. Today 6, 387–391.

    Article  PubMed  CAS  Google Scholar 

  • Warrick J. M., Chan H. Y., Gray-Board G. L., Chai Y., Paulson H. L., and Bonini N. M. (1999) Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nat. Genet. 23, 425–428.

    Article  PubMed  CAS  Google Scholar 

  • Wellington C. L. and Hayden M. R. (1997) Of molecular interactions, mice and mechanisms: new insights into Huntington’s disease. Curr. Opin. Neurol. 10, 291–298.

    Article  PubMed  CAS  Google Scholar 

  • Wellington C. L., Ellerby L. M., Hackam A. S., Margolis R. L., Trifiro M. A., Singaraja R., et al. (1998) Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract. J. Biol. Chem. 273, 9158–9167.

    Article  PubMed  CAS  Google Scholar 

  • Wellington C. L., Singaraja R., Ellerby L., Savill J., Roy S., Leavitt B., et al. (2000) Inhibiting caspase cleavage of huntingtin reduces toxicity and aggregate formation in neuronal and nonneuronal cells. J. Biol. Chem. 275, 19831–19838.

    Article  PubMed  CAS  Google Scholar 

  • Wen F. C., Li Y. H., Tsai H. F., Lin C. H., Li C., Liu C. S., et al. (2003 Down-regulation of heat shock protein 27 in neuronal cells and non-neuronal cells expressing mutant ataxin-3. FEBS Lett. 546, 307–314.

    Article  PubMed  CAS  Google Scholar 

  • Wickner S., Maurizi M. R., and Gottesman S. (1999) Post-translational quality control: folding, refolding, and degrading proteins. Science 286, 1888–1893.

    Article  PubMed  CAS  Google Scholar 

  • Wiederkehr T., Bukau B., and Buchberger A. (2002) Protein turnover: a CHIP programmed for proteolysis. Curr. Biol. 12, R26-R28.

    Article  PubMed  CAS  Google Scholar 

  • Wu Z. L., O’Kane T. M., Scott R. W., Savage M. J., and Bozyczko-Coyne D. (2002) Protein tyrosine phosphatases are up-regulated and participate in cell death induced by polyglutamine expansion. J. Biol. Chem. 277, 44208–44213.

    Article  PubMed  CAS  Google Scholar 

  • Wyttenbach A., Carmichael J., Swartz J., Furlong R. A., Narain Y., Rankin J., and Rubinsztein D. C. (2000) Effects of heat shock, heat shock protein 40 (HDJ-2) and proteasome inhibition on protein aggregation in cellular models of Huntington’s disease. Proc. Natl. Acad. Sci. USA 97, 2898–2903.

    Article  PubMed  CAS  Google Scholar 

  • Wyttenbach A., Sauvageot O., Carmichael J., Diaz-Latoud C., Arrigo A. P., and Rubinsztein D. C. (2002) Heat shock protein 27 prevents cellular polyglutamine toxicity and suppresses the increase of reactive oxygen species caused by huntingtin. Hum. Mol. Genet. 11, 1137–1151.

    Article  PubMed  CAS  Google Scholar 

  • Wyttenbach A., Swartz J., Kita H., Thykjaer T., Carmichael J., Bradley J., et al. (2001) Polyglutamine expansions cause decreased CRE-mediated transcription and early gene expression changes prior to cell death in a inducible cell model of Huntington’s disease. Hum. Mol. Genet. 10, 1829–1845.

    Article  PubMed  CAS  Google Scholar 

  • Xanthoudakis S., Roy S., Rasper D., Hennessey T., Aubin Y., Cassady R., et al. (1999) Hsp60 accelerates the maturation of pro-caspase 3 by upstream activator proteases during apoptosis. EMBO J. 18, 2049–2056.

    Article  PubMed  CAS  Google Scholar 

  • Xue L., Fletcher G. C., and Tolkovsky A. M. (1999) Autophagy is activated by apoptotic signalling in sympathetic neurons: an alternative mechanism of death execution. Mol. Cell. Neurosci. 14, 180–198.

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto A., Lucas J. J., and Hen R. (2000) Reversal of neuropathology and motor dysfunction in a conditional model of Huntington’s disease. Cell 101, 57–66.

    Article  PubMed  CAS  Google Scholar 

  • Yan L. J., Christians E. S., Liu L., Xiao X., Sohal R. S., and Benjamin I. J. (2002) Mouse heat shock transcription factor 1 deficiency alters cardiac redox homeostasis and increases mitochondrial oxidative damage. EMBO J. 21, 5164–5172.

    Article  PubMed  CAS  Google Scholar 

  • Yang W., Dunlap J. R., Andrews R. B., and Wetzel R. (2002) Aggregated polyglutamine peptides delivered to nuclei are toxic to mammalian cells. Hum. Mol. Genet. 11, 2905–2917.

    Article  PubMed  CAS  Google Scholar 

  • Yasuda S., Inoue K., Hirabayashi M., Higashiyama H., Yamamoto Y., and Fuyuhiro H. (1999) Triggering of neuronal cell death by accumulation of activated SEK1 on nuclear polyglutamine aggregations in PML bodies. Genes Cells 4, 743–756.

    Article  PubMed  CAS  Google Scholar 

  • Zabel C., Chamrad D. C., Priller J., Woodman B., Meyer H. E., Bates G. P., and Klose J. (2002) Alterations in the mouse and human proteome caused by Huntington’s disease. Mol. Cell. Proteomics 15, 366–375.

    Article  CAS  Google Scholar 

  • Zander C., Takahashi J., El Hachimi K. H., Fujigasaki H., Albanese V., Lebre A. S., et al. (2001) Similarities between spinocerebellar ataxia type 7 (SCA7) cell models and human brain: proteins recruited in inclusions and activation of caspase-3. Hum. Mol. Genet. 10, 2569–2579.

    Article  PubMed  CAS  Google Scholar 

  • Zemskov E. A., Jana N. R., Kurosawa M., Miyazaki H., Sakamoto N., Nekooki M., and Nukina N. (2003) Pro-apoptotic protein kinase C delta is associated with intranuclear inclusions in a transgenic model of Huntington’s disease. J. Neurochem. 87, 395–406.

    Article  PubMed  CAS  Google Scholar 

  • Zeron M. M., Hansson O., Chen N., Wellington C. L., Leavitt B. R., Brundin P., et al. (2002) Increased sensitivity to N-methyl-D-aspartate receptor-mediated excitotoxicity in a mouse model of Huntington’s disease. Neuron 33, 849–860.

    Article  PubMed  CAS  Google Scholar 

  • Zhou H., Cao F., Wang Z., Yu Z. X., Nguyen H. P., Evans J., Li S. H., and Li X. (2003) Huntingtin forms toxic NH2-terminal fragment complexes that are promoted by the age-dependent decrease in proteasome activity. J. Cell. Biol. 163, 109–118.

    Article  PubMed  CAS  Google Scholar 

  • Zhou H., Li S. H., and Li X. J. (2001) Chaperone suppression of cellular toxicity of huntingtin is independent of polyglutamine aggregation. J. Biol. Chem. 276, 48417–48424.

    PubMed  CAS  Google Scholar 

  • Zoghbi H. Y. and Orr H. T. (2000) Glutamine repeats and neurodegeneration. Annu. Rev. Neurosci. 23, 217–247.

    Article  PubMed  CAS  Google Scholar 

  • Zuccato C., Ciammola A., Rigamonti D., Leavitt B. R, Goffredo D., Conti L., et al. (2001) Loss of huntingtin-mediated BDNF gene transcription in Huntington’s disease. Science 293, 493–498.

    Article  PubMed  CAS  Google Scholar 

  • Zuccato C., Tartari M., Crotti A., Goffredo D., Valenza M., Conti L., et al. (2003) Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nat. Genet. 35, 76–83.

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Biochemistry, University of Cambridge, CB2 1QW, Cambridge, UK

    Andreas Wyttenbach

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Wyttenbach, A. Role of heat shock proteins during polyglutamine neurodegeneration. J Mol Neurosci 23, 69–95 (2004). https://doi.org/10.1385/JMN:23:1-2:069

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