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PMID: 12189209 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Review

Molecular chaperones as modulators of polyglutamine protein aggregation and toxicity.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 99 Suppl 4 ·2002-12-10 ·Pages 16412-8

Sakahira H, Breuer P, Hayer-Hartl MK, Hartl FU

Abstract

The formation of insoluble protein aggregates in neurons is a hallmark of neurodegenerative diseases caused by proteins with expanded polyglutamine (polyQ) repeats. However, the mechanistic relationship between polyQ aggregation and its toxic effects on neurons remains unclear. Two main hypotheses have been put forward for how polyQ expansions may cause cellular dysfunction. In one model neurotoxicity results from the ability of polyQ-expanded proteins to recruit other important cellular proteins with polyQ stretches into the aggregates. In the other model, aggregating polyQ proteins partially inhibit the ubiquitin-proteasome system for protein degradation. These two mechanisms are not exclusive but may act in combination. In general, protein misfolding and aggregation are prevented by the machinery of molecular chaperones. Some chaperones such as the members of the Hsp70 family also modulate polyQ aggregation and suppress its toxicity. These recent findings suggest that an imbalance between the neuronal chaperone capacity and the production of potentially dangerous polyQ proteins may trigger the onset of polyQ disease.

MeSH Terms
Animals Cysteine Endopeptidases/metabolism Humans Molecular Chaperones/physiology Multienzyme Complexes/metabolism Peptides/metabolism,toxicity Proteasome Endopeptidase Complex Protein Binding Transcription, Genetic Ubiquitin/metabolism
Chemicals
Molecular Chaperones Multienzyme Complexes Peptides Ubiquitin polyglutamine Cysteine Endopeptidases Proteasome Endopeptidase Complex
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Sakahira Hideki
Max-Planck-Institut für Biochemie, Department of Cellular Biochemistry, Am Klopferspitz 18a, D-82152 Martinsried, Germany.
Breuer Peter
Hayer-Hartl Manajit K
Hartl F Ulrich
References (83)
83 references, click to expand
  1. Disruption of CREB function in brain leads to neurodegeneration.
    Nat Genet. 2002 May;31(1):47-54 PMID: 11967539
  2. Chaperoning brain degeneration.
    Proc Natl Acad Sci U S A. 2002 Dec 10;99 Suppl 4:16407-11 PMID: 12149445
  3. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group.
    Cell. 1993 Mar 26;72(6):971-83 PMID: 8458085
  4. Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases.
    Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5355-8 PMID: 8202492
  5. Hsp70 and aging.
    Experientia. 1994 Nov 30;50(11-12):1092-8 PMID: 7988669
  6. Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes.
    Cell. 1995 Jun 2;81(5):811-23 PMID: 7774020
  7. Membrane fusion and the cell cycle: Cdc48p participates in the fusion of ER membranes.
    Cell. 1995 Sep 22;82(6):885-93 PMID: 7553849
  8. Expanded polyglutamine in the Machado-Joseph disease protein induces cell death in vitro and in vivo.
    Nat Genet. 1996 Jun;13(2):196-202 PMID: 8640226
  9. Involvement of the molecular chaperone Ydj1 in the ubiquitin-dependent degradation of short-lived and abnormal proteins in Saccharomyces cerevisiae.
    Mol Cell Biol. 1996 Sep;16(9):4773-81 PMID: 8756635
  10. Ubiquitin-dependent degradation of certain protein substrates in vitro requires the molecular chaperone Hsc70.
    J Biol Chem. 1997 Apr 4;272(14):9002-10 PMID: 9083024
  11. Substrate specificity of the DnaK chaperone determined by screening cellulose-bound peptide libraries.
    EMBO J. 1997 Apr 1;16(7):1501-7 PMID: 9130695
  12. Modulation of intracellular protein degradation by SSB1-SIS1 chaperon system in yeast S. cerevisiae.
    FEBS Lett. 1997 Jun 9;409(2):307-11 PMID: 9202167
  13. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation.
    Cell. 1997 Aug 8;90(3):537-48 PMID: 9267033
  14. Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo.
    Cell. 1997 Aug 8;90(3):549-58 PMID: 9267034
  15. Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3.
    Neuron. 1997 Aug;19(2):333-44 PMID: 9292723
  16. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain.
    Science. 1997 Sep 26;277(5334):1990-3 PMID: 9302293
  17. Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures.
    Nature. 1997 Oct 30;389(6654):971-4 PMID: 9353120
  18. The Hsp70 and Hsp60 chaperone machines.
    Cell. 1998 Feb 6;92(3):351-66 PMID: 9476895
  19. Truncated N-terminal fragments of huntingtin with expanded glutamine repeats form nuclear and cytoplasmic aggregates in cell culture.
    Hum Mol Genet. 1998 May;7(5):783-90 PMID: 9536081
  20. Isolation of neuronal cells with high processing activity for the Machado-Joseph disease protein.
    Cell Death Differ. 2001 Aug;8(8):871-3 PMID: 11526441
  21. Polyglutamine expansions cause decreased CRE-mediated transcription and early gene expression changes prior to cell death in an inducible cell model of Huntington's disease.
    Hum Mol Genet. 2001 Aug 15;10(17):1829-45 PMID: 11532992
  22. Review: mechanisms of disaggregation and refolding of stable protein aggregates by molecular chaperones.
    J Struct Biol. 2001 Aug;135(2):84-93 PMID: 11580258
  23. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila.
    Nature. 2001 Oct 18;413(6857):739-43 PMID: 11607033
  24. Cooperation of a ubiquitin domain protein and an E3 ubiquitin ligase during chaperone/proteasome coupling.
    Curr Biol. 2001 Oct 16;11(20):1569-77 PMID: 11676916
  25. Initial process of polyglutamine aggregate formation in vivo.
    Genes Cells. 2001 Oct;6(10):887-97 PMID: 11683917
  26. Mobilization of processed, membrane-tethered SPT23 transcription factor by CDC48(UFD1/NPL4), a ubiquitin-selective chaperone.
    Cell. 2001 Nov 30;107(5):667-77 PMID: 11733065
  27. The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol.
    Nature. 2001 Dec 6;414(6864):652-6 PMID: 11740563
  28. CHIP is a chaperone-dependent E3 ligase that ubiquitylates unfolded protein.
    EMBO Rep. 2001 Dec;2(12):1133-8 PMID: 11743028
  29. Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70.
    Nat Genet. 1999 Dec;23(4):425-8 PMID: 10581028
  30. Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice.
    Neuron. 1999 Dec;24(4):879-92 PMID: 10624951
  31. Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1.
    Nat Neurosci. 2000 Feb;3(2):157-63 PMID: 10649571
  32. Protein-only inheritance in yeast: something to get [PSI+]-ched about.
    Trends Cell Biol. 2000 Mar;10(3):98-105 PMID: 10675903
  33. Aggregation of huntingtin in yeast varies with the length of the polyglutamine expansion and the expression of chaperone proteins.
    Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1589-94 PMID: 10677504
  34. Amyloid fibrillogenesis: themes and variations.
    Curr Opin Struct Biol. 2000 Feb;10(1):60-8 PMID: 10679462
  35. Long glutamine tracts cause nuclear localization of a novel form of huntingtin in medium spiny striatal neurons in HdhQ92 and HdhQ111 knock-in mice.
    Hum Mol Genet. 2000 Mar 1;9(4):503-13 PMID: 10699173
  36. Genetic suppression of polyglutamine toxicity in Drosophila.
    Science. 2000 Mar 10;287(5459):1837-40 PMID: 10710314
  37. Two-dimensional structure of beta-amyloid(10-35) fibrils.
    Biochemistry. 2000 Mar 28;39(12):3491-9 PMID: 10727245
  38. Reversal of neuropathology and motor dysfunction in a conditional model of Huntington's disease.
    Cell. 2000 Mar 31;101(1):57-66 PMID: 10778856
  39. Decreased expression of striatal signaling genes in a mouse model of Huntington's disease.
    Hum Mol Genet. 2000 May 22;9(9):1259-71 PMID: 10814708
  40. Polyglutamine aggregates alter protein folding homeostasis in Caenorhabditis elegans.
    Proc Natl Acad Sci U S A. 2000 May 23;97(11):5750-5 PMID: 10811890
  41. Glutamine repeats and neurodegeneration.
    Annu Rev Neurosci. 2000;23:217-47 PMID: 10845064
  42. The 26S proteasome: a molecular machine designed for controlled proteolysis.
    Annu Rev Biochem. 1999;68:1015-68 PMID: 10872471
  43. Hsp70 and hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils.
    Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):7841-6 PMID: 10859365
  44. Nucleated conformational conversion and the replication of conformational information by a prion determinant.
    Science. 2000 Aug 25;289(5483):1317-21 PMID: 10958771
  45. Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription.
    Nat Genet. 2000 Sep;26(1):29-36 PMID: 10973244
  46. Mechanisms of amyloidogenesis.
    Nat Struct Biol. 2000 Oct;7(10):824-6 PMID: 11017183
  47. Identification of genes that modify ataxin-1-induced neurodegeneration.
    Nature. 2000 Nov 2;408(6808):101-6 PMID: 11081516
  48. Multiple quantum solid-state NMR indicates a parallel, not antiparallel, organization of beta-sheets in Alzheimer's beta-amyloid fibrils.
    Proc Natl Acad Sci U S A. 2000 Nov 21;97(24):13045-50 PMID: 11069287
  49. Mechanisms of chaperone suppression of polyglutamine disease: selectivity, synergy and modulation of protein solubility in Drosophila.
    Hum Mol Genet. 2000 Nov 22;9(19):2811-20 PMID: 11092757
  50. Huntington's disease: the challenge for cell biologists.
    Trends Cell Biol. 2000 Dec;10(12):531-6 PMID: 11121745
  51. Cellular defenses against unfolded proteins: a cell biologist thinks about neurodegenerative diseases.
    Neuron. 2001 Jan;29(1):15-32 PMID: 11182078
  52. An amyloid-forming peptide from the yeast prion Sup35 reveals a dehydrated beta-sheet structure for amyloid.
    Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2375-80 PMID: 11226247
  53. Interference by huntingtin and atrophin-1 with cbp-mediated transcription leading to cellular toxicity.
    Science. 2001 Mar 23;291(5512):2423-8 PMID: 11264541
  54. Identities of sequestered proteins in aggregates from cells with induced polyglutamine expression.
    J Cell Biol. 2001 Apr 16;153(2):283-94 PMID: 11309410
  55. Beyond the Qs in the polyglutamine diseases.
    Genes Dev. 2001 Apr 15;15(8):925-32 PMID: 11316786
  56. Proteins are unfolded on the surface of the ATPase ring before transport into the proteasome.
    Mol Cell. 2001 Dec;8(6):1339-49 PMID: 11779508
  57. Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson's disease.
    Science. 2002 Feb 1;295(5556):865-8 PMID: 11823645
  58. Identification of ter94, Drosophila VCP, as a modulator of polyglutamine-induced neurodegeneration.
    Cell Death Differ. 2002 Mar;9(3):264-73 PMID: 11859409
  59. Molecular chaperones enhance the degradation of expanded polyglutamine repeat androgen receptor in a cellular model of spinal and bulbar muscular atrophy.
    Hum Mol Genet. 2002 Mar 1;11(5):515-23 PMID: 11875046
  60. Molecular chaperones in the cytosol: from nascent chain to folded protein.
    Science. 2002 Mar 8;295(5561):1852-8 PMID: 11884745
  61. Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases.
    Nature. 2002 Apr 4;416(6880):507-11 PMID: 11932737
  62. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
    Nature. 2002 Apr 4;416(6880):535-9 PMID: 11932745
  63. Amyloid fibers are water-filled nanotubes.
    Proc Natl Acad Sci U S A. 2002 Apr 16;99(8):5591-5 PMID: 11960014
  64. Recruitment of a 19S proteasome subcomplex to an activated promoter.
    Science. 2002 Apr 19;296(5567):548-50 PMID: 11964484
  65. Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1.
    Nat Genet. 1998 Jun;19(2):148-54 PMID: 9620770
  66. Intranuclear neuronal inclusions in Huntington's disease and dentatorubral and pallidoluysian atrophy: correlation between the density of inclusions and IT15 CAG triplet repeat length.
    Neurobiol Dis. 1998 Apr;4(6):387-97 PMID: 9666478
  67. Hsp104, Hsp70, and Hsp40: a novel chaperone system that rescues previously aggregated proteins.
    Cell. 1998 Jul 10;94(1):73-82 PMID: 9674429
  68. A cellular model that recapitulates major pathogenic steps of Huntington's disease.
    Hum Mol Genet. 1998 Sep;7(9):1355-61 PMID: 9700187
  69. Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice.
    Cell. 1998 Oct 2;95(1):41-53 PMID: 9778246
  70. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions.
    Cell. 1998 Oct 2;95(1):55-66 PMID: 9778247
  71. J proteins catalytically activate Hsp70 molecules to trap a wide range of peptide sequences.
    Mol Cell. 1998 Nov;2(5):593-603 PMID: 9844632
  72. Recruitment and the role of nuclear localization in polyglutamine-mediated aggregation.
    J Cell Biol. 1998 Dec 14;143(6):1457-70 PMID: 9852144
  73. The fundamentals of protein folding: bringing together theory and experiment.
    Curr Opin Struct Biol. 1999 Feb;9(1):92-101 PMID: 10047588
  74. Evidence for proteasome involvement in polyglutamine disease: localization to nuclear inclusions in SCA3/MJD and suppression of polyglutamine aggregation in vitro.
    Hum Mol Genet. 1999 Apr;8(4):673-82 PMID: 10072437
  75. Glutamine repeats and neurodegenerative diseases: molecular aspects.
    Trends Biochem Sci. 1999 Feb;24(2):58-63 PMID: 10098399
  76. Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: implications for Huntington's disease pathology.
    Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4604-9 PMID: 10200309
  77. Insoluble detergent-resistant aggregates form between pathological and nonpathological lengths of polyglutamine in mammalian cells.
    Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11404-9 PMID: 10500189
  78. Mechanisms underlying ubiquitination.
    Annu Rev Biochem. 2001;70:503-33 PMID: 11395416
  79. Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation.
    Mol Biol Cell. 2001 May;12(5):1393-407 PMID: 11359930
  80. Impairment of the ubiquitin-proteasome system by protein aggregation.
    Science. 2001 May 25;292(5521):1552-5 PMID: 11375494
  81. Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington's disease.
    Hum Mol Genet. 2001 Jun 1;10(12):1307-15 PMID: 11406612
  82. Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice.
    Hum Mol Genet. 2001 Jul 1;10(14):1511-8 PMID: 11448943
  83. Valosin-containing protein is a multi-ubiquitin chain-targeting factor required in ubiquitin-proteasome degradation.
    Nat Cell Biol. 2001 Aug;3(8):740-4 PMID: 11483959
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.182426899
Published
2002-12-10
Epub
2002-00-20
Pages
16412-8
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC139902
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.182426899 PMC Full Text View journal details
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