Journal of Molecular Medicine

, Volume 81, Issue 11, pp 678–699 | Cite as

Protein aggregation and aggregate toxicity: new insights into protein folding, misfolding diseases and biological evolution

  • Massimo StefaniEmail author
  • Christopher M. Dobson
Invited review


The deposition of proteins in the form of amyloid fibrils and plaques is the characteristic feature of more than 20 degenerative conditions affecting either the central nervous system or a variety of peripheral tissues. As these conditions include Alzheimer's, Parkinson's and the prion diseases, several forms of fatal systemic amyloidosis, and at least one condition associated with medical intervention (haemodialysis), they are of enormous importance in the context of present-day human health and welfare. Much remains to be learned about the mechanism by which the proteins associated with these diseases aggregate and form amyloid structures, and how the latter affect the functions of the organs with which they are associated. A great deal of information concerning these diseases has emerged, however, during the past 5 years, much of it causing a number of fundamental assumptions about the amyloid diseases to be re-examined. For example, it is now apparent that the ability to form amyloid structures is not an unusual feature of the small number of proteins associated with these diseases but is instead a general property of polypeptide chains. It has also been found recently that aggregates of proteins not associated with amyloid diseases can impair the ability of cells to function to a similar extent as aggregates of proteins linked with specific neurodegenerative conditions. Moreover, the mature amyloid fibrils or plaques appear to be substantially less toxic than the pre-fibrillar aggregates that are their precursors. The toxicity of these early aggregates appears to result from an intrinsic ability to impair fundamental cellular processes by interacting with cellular membranes, causing oxidative stress and increases in free Ca2+ that eventually lead to apoptotic or necrotic cell death. The 'new view' of these diseases also suggests that other degenerative conditions could have similar underlying origins to those of the amyloidoses. In addition, cellular protection mechanisms, such as molecular chaperones and the protein degradation machinery, appear to be crucial in the prevention of disease in normally functioning living organisms. It also suggests some intriguing new factors that could be of great significance in the evolution of biological molecules and the mechanisms that regulate their behaviour.


Amyloid aggregates Amyloidoses Molecular evolution Folding and disease Protein aggregation 



Endoplasmic reticulum


Heat-shock protein


N-terminal domain of hydrogenase maturation factor HypF


Reactive oxygen species


Src-homology 3



This work was supported in part by the Italian MIUR (PRIN 2001 "New functional roles, folding and structural biology of prokaryotic sulfotransferases" and PRIN 2002 "Protein folding and misfolding: biogenesis, structure and cytotoxicity of protein aggregates"). The research of CMD is supported in part by a Programme Grant from the Wellcome Trust.


  1. 1.
    Levinthal C (1968) Are there pathways for protein folding? J Chem Phys 85:44–45Google Scholar
  2. 2.
    Radford SE, Dobson CM (1999) From computer simulations to human disease: emerging themes in protein folding. Cell 97:291–298PubMedGoogle Scholar
  3. 3.
    Uversky VN (2002) Natively unfolded proteins: a point where biology waits for physics. Protein Sci 11:739–756PubMedGoogle Scholar
  4. 4.
    Thomas PJ, Qu BH, Pedersen PL (1995) Defective protein folding as a basis of human disease. Trends Biochem Sci 20:456–459PubMedGoogle Scholar
  5. 5.
    Clark EDB (1998) Refolding of recombinants proteins. Curr Opin Biotechnol 9:157–163)PubMedGoogle Scholar
  6. 6.
    Jiménez JL, Guijarro JI, Orlova E, Zurdo J, Dobson CM, Sunde M, Saibil HR (1999) Cryo-electron microscopy structure of an SH3 amyloid fibril and model of the molecular packing. EMBO J 18:815–821PubMedGoogle Scholar
  7. 7.
    Kelly J (1998) Alternative conformation of amyloidogenic proteins and their multi-step assembly pathways. Curr Opin Struct Biol 8:101–106Google Scholar
  8. 8.
    Dobson CM (2001) The structural basis of protein folding and its links with human disease Philos Trans R Soc Lond B 356:133–145Google Scholar
  9. 9.
    Horssen J van, Wilhelmus MM, Heljasvaara R, Pihlajaniemi T, Wesseling P, de Waal RM, Verbeek MM (2002) Collagen XVIII: a novel heparan sulfate proteoglycan associated with vascular amyloid. depositions and senile plaques in Alzheimer's disease brains. Brain Pathol 12:456–462PubMedGoogle Scholar
  10. 10.
    Diaz-Nido J, Wandosell F, Avila J (2002) Glycosaminoglycans and beta-amyloid, prion and tau peptides in neurodegenerative diseases. Peptides 23:1323–1332PubMedGoogle Scholar
  11. 11.
    Pepys MB, Herbert J, Hutchinson WL, Tennent GA, Lachmann HJ, Gallimore JR, Lovat LB, Bartfal T, Alanine A, Hertel C, Hofmann T, Jakob-Roetne R, Norcross RD, Kemp JA, Yamamura K, Suzuki M, Taylor GW, Murray S, Thompson D, Purvis A, Kolstoe S, Wood SP, Hawkins PN (2002) Targeted pharmaceutical depletion of serum amyloid P component for treatment of human amyloidosis. Nature 417:254–259Google Scholar
  12. 12.
    Reilly MM (1998) Genetically determined neuropathies J Neurol 245:6–13Google Scholar
  13. 13.
    Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I, Trommer B, Viola KL, Wals P, Zhang C, Finch CE, Krafft GA, Klein WL (1998) Diffusible nonfibrillar ligands derived from Aβ-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci USA 95:6448–6453PubMedGoogle Scholar
  14. 14.
    Hartley D, Walsh DM, Ye CP, Diehl T, Vasquez S, Vassilev PM (1999) Protofibrillar intermediates of amyloid β-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. J Neurosci 19:8876–8884PubMedGoogle Scholar
  15. 15.
    Walsh DM, Hartley DM, Kusumoto Y, Fezoui Y, Condron MM, Lomakin A, Benedek GB, Selkoe DJ, Teplow DB (1999) Amyloid β-protein fibrillogenesis. Structure and biological activity of protofibrillar intermediates. J Biol Chem 274:25945–25952PubMedGoogle Scholar
  16. 16.
    Monji A, Yoshida I, Tashiro KI, Hayashi Y, Matsuda K, Tashiro N (2000) Inhibition of Aβ fibril formation and Aβ-induced cytotoxicity by senile plaque-associated proteins. Neurosci Lett 278:81–84PubMedGoogle Scholar
  17. 17.
    Goldberg MS, Lansbury PT (2000) Is there a cause-and-effect relationship between alpha-synuclein fibrillization and Parkinson's disease? Nat Cell Biol 2:E115–E119PubMedGoogle Scholar
  18. 18.
    Conway KA, Lee SJ, Rochet JC, Ding TT, Williamson RE, Lansbury PT (2000) Acceleration of oligomerization not fibrillization is a shared property of both alpha-synuclein mutations linked to early-onset Parkinson's disease. Implication for pathogenesis and therapy Proc Natl Acad Sci USA 97:571–576Google Scholar
  19. 19.
    Lin H, Zhu YJ, Lal R (1999) Amyloid β protein (1–40) forms calcium-permeable Zn2+-sensitive channel in reconstituted lipid vesicles. Biochemistry 38:11189–11196PubMedGoogle Scholar
  20. 20.
    Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ (2002) Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416:535–539PubMedGoogle Scholar
  21. 21.
    Lorenzo A, Yankner BA (1994) β-Amyloid neurotoxicity requires fibril formation and is inhibited by Congo red. Proc Natl Acad Sci USA 91:12243–12247PubMedGoogle Scholar
  22. 22.
    Thomas T, Thomas G, McLendon C, Sutton T, Mullan M (1996) β-Amyloid-mediated vasoactivity and vascular endothelial damage. Nature 380:168–171Google Scholar
  23. 23.
    Pepys MB (1995) in: Weatherall DJ, Ledingham JG, Warrel DA (eds) Oxford textbook of medicine, 3rd edn. Oxford University Press, Oxford, pp 1512–1524Google Scholar
  24. 24.
    Clarke G, Collins RA, Leavitt BR, Andrews DF, Hayden MR, Lumsden CJ, McInnes RR (2000) A one-hit model of cell death in inherited neuronal degeneration. Nature 406:195–199PubMedGoogle Scholar
  25. 25.
    Perutz MF, Windle AH (2001) Cause of neuronal death in neurodegenerative diseases attributable to expansion of glutamine repeats. Nature 412:143–144PubMedGoogle Scholar
  26. 26.
    Sherman MY, Goldberg AL (2001) Cellular defenses against unfolded proteins: a cell biologist thinks about neurodegenerative diseases. Neuron 29:15–32PubMedGoogle Scholar
  27. 27.
    Pelham HR (1986) Speculations on the functions of the major heat shock and glucose-regulated proteins. Cell 46:959–961PubMedGoogle Scholar
  28. 28.
    Ellis RJ, van der Vies SM, Hemmingsen SM (1989) The molecular chaperone concept. Biochem Soc Symp 55:145–153PubMedGoogle Scholar
  29. 29.
    Keller JN, Hanni KB, Markesbery WR (2000) Impaired proteasome function in Alzheimer's disease. J Neurochem 75:436–439CrossRefPubMedGoogle Scholar
  30. 30.
    McNaught K, Jenner P (2001) Proteasomal function is impaired in substantia nigra in Parkinson's disease. Neurosci Lett 297:191–194PubMedGoogle Scholar
  31. 31.
    Tanaka Y, Engelender S, Igarashi S, Rao RK, Wenner T, Tanzi RE, Sawa A, Sawson VL, Dawson TM, Ross CA (2001) Inducible expression of mutant α-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis Hum Mol Genet 10:919–926Google Scholar
  32. 32.
    Shimura H, Schlossmacher MG, Hattori N, Frosch MP, Trockenbacher A, Schneider R, Mizuno Y, Kosik KS, Selkoe DJ (2001) Ubiquitination of a new form of α-synuclein by parkin from human brain: implications for Parkinson's disease. Science 293:263–269PubMedGoogle Scholar
  33. 33.
    Schubert U, Antòn LC, Gibbs J, Orbyry CC, Yewdell JW, Bennink JR (2000) Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature 404:770–774PubMedGoogle Scholar
  34. 34.
    Reits EAJ, Vos JC, Grommé M, Neefjes J (2000) The major substrates for TAP in vivo are derived from newly synthesized proteins. Nature 404:774–778CrossRefPubMedGoogle Scholar
  35. 35.
    Plemper RK, Wolf DH (1999) Retrograde protein translocation: eradication of secretory proteins in health and disease. Trends Biochem Sci 24:266–270PubMedGoogle Scholar
  36. 36.
    Booth DR, Sunde M, Bellotti V, Robinson CV, Hutchinson WL, Fraser PE, Hawkins PN, Dobson CM, Radford SE, Blake CF, Pepys MB (1997) Instability, unfolding and aggregation of human lysozyme variants underlying amyloid fibrillogenesis. Nature 385:787–793Google Scholar
  37. 37.
    Chiti F, Mangione P, Andreola A, Giorgetti S, Stefani M, Dobson CM, Bellotti V, Taddei N (2001) Detection of two partially structured species in the folding process of the amyloidogenic protein β2-microglobulin. J Mol Biol 307:379–391PubMedGoogle Scholar
  38. 38.
    Serpell LC, Sunde M, Benson MD, Tennent GA, Pepys MB, Fraser PE (2000) The protofilament substructure of amyloid fibrils. J Mol Biol 300:1033–1039PubMedGoogle Scholar
  39. 39.
    Serpell LS (2000) Alzheimer's amyloid fibrils: structure and assembly. Biochim Biophys Acta 1502:16–30PubMedGoogle Scholar
  40. 40.
    Wetzel R (2002) Ideas of order for amyloid fibril structure. Structure 10:1031–1036PubMedGoogle Scholar
  41. 41.
    Kourie JI, Farrelly PV, Henry CL (2001) Channel activity of deamidated isoforms of prion protein fragment 106–126 in planar lipid bilayers. Neurosci Res 66:214–220PubMedGoogle Scholar
  42. 42.
    Chamberlain AK, MacPhee CE, Zurdo J, Morozova-Roche LA, Hill HA, Dobson CM, Davis JJ (2000) Ultrastructural organization of amyloid fibrils by atomic force microscopy. Biophys J 79:3282–3293PubMedGoogle Scholar
  43. 43.
    Petkova AT, Ishii Y, Balbach JJ, Antzutkin ON, Leapman RD, Delaglio F, Tycko R (2002) A structural model for Alzheimer's β-amyloid fibrils based on experimental constraints from solid state NMR. Proc Natl Acad Sci USA 99:16742–16747PubMedGoogle Scholar
  44. 44.
    Jiménez JL, Nettleton EJ, Bouchard M, Robinson CV, Dobson CM, Saibil HR (2002) The protofilament structure of insulin amyloid fibrils. Proc Natl Acad Sci USA 99:9196–9201PubMedGoogle Scholar
  45. 45.
    Lin H, Bhatia R, Lal R (2001) Amyloid β protein forms ion channels: implications for Alzheimer's disease pathophysiology. FASEB J 15:2433–2444PubMedGoogle Scholar
  46. 46.
    Lashuel HA, Petre BM, Wall J, Simon M, Nowak RJ, Walz T, Lansbury PT (2002) α-Synuclein, especially the Parkinson's disease-associated mutants, forms pore-like annular and tubular protofibrils. J Mol Biol 322:1089–1102PubMedGoogle Scholar
  47. 47.
    Poirier MA, Li H, Macosko J, Cail S, Amzel M, Ross CA (2002) Huntingtin spheroids and protofibrils as precursors in polyglutamine fibrillization. J Biol Chem 277:41032–41037PubMedGoogle Scholar
  48. 48.
    Hirakura Y, Kagan BL (2001) Pore formation by beta-2-microglobulin: a mechanism for the pathogenesis of dialysis-associated amyloidosis. Amyloid 8:94–100PubMedGoogle Scholar
  49. 49.
    Quintas A, Vaz DC, Cardoso I, Saraiva MJ M, Brito RMM (2001) Tetramer dissociation and monomer partial unfolding precedes protofibril formation in amyloidogenic transthyretin variants. J Biol Chem 276:27207–27213PubMedGoogle Scholar
  50. 50.
    Bucciantini M, Giannoni E, Chiti F, Baroni F, Formigli L, Zurdo J, Taddei N, Ramponi G, Dobson CM, Stefani M (2002) Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature 416:507–511CrossRefPubMedGoogle Scholar
  51. 51.
    Kayed R, Head E, Thompson JL, McIntire TM, Milton SC, Cotman CW, Glabe CG (2003) Common structure of soluble amyloid oligomers implies common mechanisms of pathogenesis. Science 300:486–489PubMedGoogle Scholar
  52. 52.
    Chapman MR, Robinson LS, Pinkner JS, Roth R, Heuser J, Hammar M, Normark S, Hultgren SJ (2002) Role of Escherichia coli curli operons in directing amyloid fiber formation. Science 295:851–855PubMedGoogle Scholar
  53. 53.
    Frederikse PH (2000) Amyloid-like protein structure in mammalian ocular lenses. Curr Eye Res 20:462–468PubMedGoogle Scholar
  54. 54.
    Hirakura Y, Carreras I, Sipe JD, Kagan BL (2002) Channel formation by serum amyloid A: a potential mechanism for amyloid pathogenesis and host defense. Amyloid 9:13–23PubMedGoogle Scholar
  55. 55.
    Svensson M, Sabharwal H, Hakansson A, Mossberg, AK, Lipniunas P, Leffler H, Svanborg C, Linset S (1999) Molecular characterization of α-lactalbumin folding variants that induce apoptosis in tumor cells. J Biol Chem 274:6388–6396PubMedGoogle Scholar
  56. 56.
    Glenner GG, Ein D, Eanes ED, Bladen HA, Terry W, Page DL (1971) Creation of amyloid fibrils from Bence Jones proteins in vitro. Science 174:712–714PubMedGoogle Scholar
  57. 57.
    Colon W, Kelly JW (1992) Partial denaturation of transthyretin is sufficient for amyloid fibril formation in vitro. Biochemistry 31:8654–8660PubMedGoogle Scholar
  58. 58.
    Gujiarro JI, Sunde M, Jones JA, Campbell ID, Dobson CM (1998) Amyloid fibril formation by an SH3 domain. Proc Natl Acad Sci 95:4224–4228CrossRefPubMedGoogle Scholar
  59. 59.
    Litvinovich SV, Brew SA, Aota S, Akiyama SK, Haudenschild C, Ingham KC (1998) Formation of amyloid-like fibrils by self-association of a partially unfolded fibronectin type III module. J Mol Biol 280:245–258PubMedGoogle Scholar
  60. 60.
    Chiti F, Webster P, Taddei N, Clark A, Stefani M, Ramponi G, Dobson CM (1999) Designing conditions for in vitro formation of amyloid protofilaments and fibrils. Proc Natl Acad Sci USA 96:3590–3594PubMedGoogle Scholar
  61. 61.
    Chiti F, Bucciantini M, Capanni C, Taddei N, Dobson CM, Stefani M (2001) Solution conditions can promote formation of either amyloid protofilaments or mature fibrils from the HypF N-terminal domain. Protein Sci 10:2541–2547PubMedGoogle Scholar
  62. 62.
    Tjernberg L, Hosia W, Bark N, Thyberg J, Johansson J (2002) Charge attraction and β propensity are necessary for amyloid fibril formation from tetrapeptides. J Biol Chem 277:43243–43246PubMedGoogle Scholar
  63. 63.
    Lopez De La Paz M, Goldie K, Zurdo J, Lacroix E, Dobson CM, Hoenger A, Serrano L (2002) De novo designed peptide-based amyloid fibrils. Proc Natl Acad Sci USA 99:16052–16057PubMedGoogle Scholar
  64. 64.
    Dobson CM (2003) Protein folding and disease: a view from the first Horizon Symposium. Nat Rev Drug Discov 2:154–160PubMedGoogle Scholar
  65. 65.
    Richardson JS, Richardson DC (2002) Natural β-sheet proteins use negative design to avoid edge-to-edge aggregation. Proc Natl Acad Sci USA 99:2754–2759PubMedGoogle Scholar
  66. 66.
    Broome BM, Hecht MH (2000) Nature disfavors sequences of alternating polar and non-polar amino acids: implications for amyloidogenesis. J Mol Biol 296:961–968PubMedGoogle Scholar
  67. 67.
    Schwarz R, Istrail S, King J (2001) Frequencies of amino acid strings in globular protein sequences indicate suppression of blocks of consecutive hydrophobic residues. Protein Sci 10:1023–1031PubMedGoogle Scholar
  68. 68.
    Chiti F, Taddei N, Stefani M, Dobson CM, Ramponi G (2001) Reduction of the amyloidogenicity of a protein by specific binding of ligands to the native conformation. Protein Sci 10:879–886PubMedGoogle Scholar
  69. 69.
    Ramirez-Alvarado, M, Merkel JS, Regan L (2000) A systematic exploration of the influence of the protein stability on amyloid fibril formation in vitro. Proc Natl Acad Sci USA 97:8979–8984PubMedGoogle Scholar
  70. 70.
    Taddei N, Capanni C, Chiti F, Stefani M, Dobson CM, Ramponi G (2001) Folding and aggregation are selectively influenced by the conformational preferences of the α-helices of muscle acylphosphatase. J Biol Chem 276:37149–37154PubMedGoogle Scholar
  71. 71.
    Chiti F, Calamai M, Taddei N, Stefani M, Ramponi G, Dobson CM (2002) Studies on the aggregation of mutant proteins in vitro provide insights into the genetics of amyloid diseases. Proc Natl Acad Sci USA 99 [Suppl 4]:16419–16426Google Scholar
  72. 72.
    Dobson CM (1999) Protein misfolding, evolution and disease. Trends Biochem Sci 24:329–332Google Scholar
  73. 73.
    Minton AP (1994) Influence of macromolecular crowding on intracellular association reactions: possible role in volume regulation. In: Strange K (ed) Cellular and molecular physiology of cell volume regulation.– CRC, Boca Raton, pp 181–190Google Scholar
  74. 74.
    Ellis RJ (2001) Macromolecular crowding: an important but neglected aspect of the intracellular environment. Curr Opin Struct Biol 11:114–119PubMedGoogle Scholar
  75. 75.
    Nagy IZ, Nagy K, Lustyik G (1982) Protein and water content of aging brain. Exp Brain Res Suppl 5:118–122Google Scholar
  76. 76.
    Conlon IJ, Dunn GA, Mudge AW, Raff MC (2001) Extracellular control of cell size. Nat Cell Biol 3:918–921PubMedGoogle Scholar
  77. 77.
    Al-Habori M (2001) Macromolecular crowding and its role as intracellular signalling of cell volume regulation. Int J Biochem Cell Biol 33:844–864CrossRefPubMedGoogle Scholar
  78. 78.
    Bhatia R, Lin H, Lal R (2000) Fresh and nonfibrillar amyloid β protein (1–42) induces rapid cellular degeneration in aged human fibroblasts: evidence for AβP-channel-mediated cellular toxicity. FASEB J 14:1233–1243PubMedGoogle Scholar
  79. 79.
    Nilsberth C, Westlind-Danielssnon A, Eckman CB, Condron MM, Axelman K, Forsell C, Stenh C, Luthman J, Teplow DB, Younkin SG, Naslund J, Lannfelt L (2001) The "arctic" APP mutation (E693G) causes Alzheimer's disease by enhanced Aβ protofibril formation. Nat Neurosci 4:887–893CrossRefPubMedGoogle Scholar
  80. 80.
    Sousa MM, Cardoso I, Fernandes R, Guimaraes A, Saraiva MJ (2001) Deposition of transthyretin in early stages of familial amyloidotic polyneuropathy. Am J Pathol 159:1993–2000Google Scholar
  81. 81.
    Katsuno M, Adachi H, Kume A, Li M, Nakagomi Y, Niwa H, Sang C, Kobayashi Y, Doyu M, Sobue G (2002) Testosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Neuron 35:843–854PubMedGoogle Scholar
  82. 82.
    Dickson DW (1995) Correlation of synaptic and pathological markers with cognition of the elderly. Neurobiol Aging 16:285–298CrossRefPubMedGoogle Scholar
  83. 83.
    Volles MJ, Lansbury PT (2001) Vesicle permeabilization by protofibrillar α-synuclein: comparison of wild-type with Parkinson's disease linked mutants and insights in the mechanisms. Biochemistry 40:7812–7819PubMedGoogle Scholar
  84. 84.
    Kourie JI (1999) Synthetic C-type mammalian natriuretic peptide forms large cation selective channels. FEBS Lett 445:57–62PubMedGoogle Scholar
  85. 85.
    Ariste N, Pollard HB, Rojas E (1993) Giant multilevel cation channels formed by Alzheimer disease amyloid beta-protein [A beta P-(1–40)] in bilayer membranes. Proc Natl Acad Sci USA 90:10573–10577PubMedGoogle Scholar
  86. 86.
    Mirzabekov TA, Lin MC, Kagan BL (1996) Pore formation by the cytotoxic islet amyloid peptide amylin. J Biol Chem 271:1988–1992PubMedGoogle Scholar
  87. 87.
    Lin MC, Mirzabekov T, Kagan BL (1997) Channel formation by a neurotoxic prion protein fragment. J Biol Chem 272:44–47PubMedGoogle Scholar
  88. 88.
    Ding TT, Lee SJ, Rochet J-C, Lansbury PT (2002) Annular α-synuclein protofibrils are produced when spherical protofibrils are incubated in solution or bound to brain-derived membranes. Biochemistry 41:10209–10217PubMedGoogle Scholar
  89. 89.
    Zhu YJ, Lin H, Lal R (2000) Fresh and nonfibrillar amyloid β protein (1–40) induces rapid cellular degeneration in aged human fibroblasts: evidence for AβP-channel-mediated cellular toxicity. FASEB J 14:1244–1254PubMedGoogle Scholar
  90. 90.
    Kourie JI, Shorthouse AA (2000) Properties of cytotoxic peptide-induced ion channels. Am J Physiol Cell Physiol 278:C1063–C1087PubMedGoogle Scholar
  91. 91.
    Kourie JI, Henry CL (2002) Ion channel formation and membrane-linked pathologies of misfolded hydrophobic proteins: the role of dangerous unchaperoned molecules. Clin Exp Pharmacol Physiol 29:741–753PubMedGoogle Scholar
  92. 92.
    Hotze EM, Heuck AP, Czajkowsky M, Shao Z, Johnson AE, Tweten R (2002) Monomer-monomer interactions drive the prepare to pore conversion of a β-barrel-forming cholesterol-dependent cytolysin. J Biol Chem 277:11597–115605PubMedGoogle Scholar
  93. 93.
    Bychkova VE, Pain RH, Ptitsyn OB (1988) The molten globule state is involved in the translocation of protein across membranes. FEBS Lett 238:231–234PubMedGoogle Scholar
  94. 94.
    Yamamoto A, Lucas JJ, Hen R (2000) Reversal of neuropathology and motor dysfunction in a conditional model of Huntington's disease Cell 101:57–66Google Scholar
  95. 95.
    Ross CA (2002) Polyglutamine pathogenesis: emergence of unifying mechanisms for Huntington's disease and related disorders. Neuron 35:819–822PubMedGoogle Scholar
  96. 96.
    Morishima Y, Gotoh Y, Zieg J, Barrett T, Takano H, Flavell R, Davis RJ, Shirasaki Y, Greenberg ME (2001) Beta-amyloid induces neuronal apoptosis via a mechanism that involves the c-Jun N-terminal kinase pathway and the induction of Fas ligand. J Neurosci 21:7551–7560PubMedGoogle Scholar
  97. 97.
    Kourie JI (2001) Mechanisms of amyloid β protein-induced modification in ion transport systems: implications for neurodegenerative diseases. Cell Mol Neurobiol 21:173–213PubMedGoogle Scholar
  98. 98.
    Butterfield AD, Drake J, Pocernich C, Castegna A (2001) Evidence of oxidative damage in Alzheimer's disease brain: central role for amyloid β-peptide. Trends Mol Med 7:548–554PubMedGoogle Scholar
  99. 99.
    Milhavet O, Lehmann S (2002) Oxidative stress and the prion protein in transmissible spongiform encephalopathies. Brain Res Brain Res Rev 38:328–339PubMedGoogle Scholar
  100. 100.
    Hyun DH, Lee, MH, Hattori N, Kubo, SI, Mizuno Y, Halliwell B, Jenner P (2002) Effect of wild-type or mutant parkin on oxidative damage, nitric oxide, antioxidant defenses, and the proteasome. J Biol Chem 277:28572–28577PubMedGoogle Scholar
  101. 101.
    Wyttenbach A, Sauvageot O, Carmichael J, Diaz-Latoud C, Arrigo, AP, Rubinsztein DC (2002) Heat shock protein 27 prevents cellular polyglutamine toxicity and suppresses the increase of reactive oxygen species caused by huntingtin. Hum Mol Genet 11:1137–1151PubMedGoogle Scholar
  102. 102.
    Guentchev M, Voigtlander T, Haberler C, Groschup MH, Budka H (2000) Evidence for oxidative stress in experimental prion disease. Neurobiol Dis 7:270–273CrossRefPubMedGoogle Scholar
  103. 103.
    Choi YG, Kim JL, Lee HP, Jin JK, Choi EK, Carp. RI, Kim YS (2000) Induction of heme oxygenase-1 in the brain of scrapie-infected mice. Neurosci Lett 11:173–176CrossRefGoogle Scholar
  104. 104.
    Zhang L, Xing, GQ, Barker JL, Chang Y, Maric D, Ma W, Li B-S, Rubinow DR (2001) α-Lipoic acid protects rat cortical neurons against cell death induced by amyloid and hydrogen peroxide through the Akt signalling pathway. Neurosci Lett 312:125–128PubMedGoogle Scholar
  105. 105.
    Lee DW, Sohn HO, Lim HB, Lee YG, Kim YS, Carp RJ, Wisnievski HM (1999) Alteration of free radical metabolism in the brain of mice infected with scrapie agent. Free Radic Res 30:499–507PubMedGoogle Scholar
  106. 106.
    Keller JN, Huang FF, Markesbery WR (2002) Decreased levels of proteasome activity and proteasome expression in aging spinal cord. Neuroscience 98:149–156CrossRefGoogle Scholar
  107. 107.
    Wyttenbach A, Sauvageot O, Carmichael J, Diaz-Latoud C, Arrigo AP, Rubinsztein DC (2002) Heat shock protein 27 prevents cellular polyglutamine toxicity and suppresses the increase of reactive oxygen species caused by huntingtin. Hum Mol Genet 11:1137–1151PubMedGoogle Scholar
  108. 108.
    Wyttenbach A, Swartz J, Kita H, Thykjaer T, Carmichael J, Bradley J, Brown R, Maxwell M, Schapira A, Orntoft TF, Kato K, Rubinsztein DC (2001) 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 10:1829–1845PubMedGoogle Scholar
  109. 109.
    Brunelle P, Rauk A (2002) The radical model of Alzheimer's disease: specific recognition of Gly29 and Gly33 by Met35 in a beta-sheet model of Abeta: an ONIOM study. J Alzheimers Dis 4:283–289PubMedGoogle Scholar
  110. 110.
    Turnbull S, Tabner BJ, El-Agnaf OMA, Moore S, Davies Y, Allsop D (2001) α-Synuclein implicated in Parkinson's disease catalyzes the formation of hydrogen peroxide in vitro. Free Radic Biol Med 30:1163–1170PubMedGoogle Scholar
  111. 111.
    Tabner BJ, Turnbull S, El-Agnaf OMA, Allsop D (2002) Formation of hydrogen peroxide and hydroxyl radicals from Aβ and α-synuclein as a possible mechanism of cell death in Alzheimer's disease and Parkinson's disease. Free Radic Biol Med 32:1076–1083PubMedGoogle Scholar
  112. 112.
    Pappolla MA, Omar RA, Chyan, YJ, Ghiso J, Hsiao K, Bozner P, Perry G, Smith MA, Cruz-Sanchez F (2001) Induction of NADPH cytochrome P450 reductase by the Alzheimer β-protein. Amyloid as a "foreign body." J Neurochem 78:121–128Google Scholar
  113. 113.
    Qin L, Liu Y, Cooper C, Liu B, Wilson B, Hong J-S (2002) Microglia enhance β-amyloid peptide-induced toxicity in cortical and mesencephalic neurons by producing reactive oxygen species. J Neurochem 83:973–983PubMedGoogle Scholar
  114. 114.
    Mattson MP (1999) Impairment of membrane transport and signal transduction systems by amyloidogenic proteins. Methods Enzymol 309:733.768PubMedGoogle Scholar
  115. 115.
    Moreira PI, Santos MS, Moreno A, Rego AC, Oliveira C (2002) Effect of amyloid beta-peptide on permeability transition pore: a comparative study. J Neurosci Res 15:257–267CrossRefGoogle Scholar
  116. 116.
    Squier TC (2001) Oxidative stress and protein aggregation during biological aging. Exp Gerontol 36:1539–1550PubMedGoogle Scholar
  117. 117.
    Kawahara M, Kuroda Y, Arispe N, Rojas E (2000) Alzheimer's β-amyloid, human islet amylin, and prion protein fragment evoke intracellular free calcium elevation by a common mechanism in a hypopthalamic GnRH neuronal cell line. J Biol Chem 275:14077–14083PubMedGoogle Scholar
  118. 118.
    Selkoe DJ (2001) Alzheimer's disease: genes, proteins, and therapy Physiol Rev 81:741–766Google Scholar
  119. 119.
    Varadarajan S, Yatin S, Aksenova M, Butterfield DA (2000) Alzheimer's amyloid β-peptide-associated free radical oxidative stress and neurotoxicity. J Struct Biol 130:184–208CrossRefPubMedGoogle Scholar
  120. 120.
    Fraser SA, Karimi R, Michalak M, Hudig D (2000) Perforin lytic activity is controlled by calreticulin. J Immunol 164:4150–4155PubMedGoogle Scholar
  121. 121.
    Morgan BP (1999) Regulation of the complement membrane attack pathway. Crit Rev Immunol 19:173–198PubMedGoogle Scholar
  122. 122.
    Reed JC (2000) Mechanisms of apoptosis. Am J Pathol 157:1415–1430PubMedGoogle Scholar
  123. 123.
    Hinshaw JE, Schmid SL (1995) Dynamin self-assembles into rings suggesting a mechanism for coated vesicle budding. Nature 374:190–192PubMedGoogle Scholar
  124. 124.
    Valeva A, Schnabell R, Valevi I, Boukhallouk F, Bhakdi S, Palmer M (2001) Membrane insertion of the heptameric staphylococcal α-toxin pore. J Biol Chem 276:14835–14841PubMedGoogle Scholar
  125. 125.
    Miyata S, Matsushita O, Minami J, Katayama S, Shimamoto S, Okabe A (2001) Cleavage of a C-terminal peptide is essential for heptamerization of Clostridium perfringens ε-toxin in the synaptosomal membrane. J Biol Chem 276:13778–13783PubMedGoogle Scholar
  126. 126.
    Tweten RK, Parker MW, Johnson AE (2001) The cholesterol-dependent cytolysins. In: Goot G van der (ed) Pore forming toxins, vol 257, Springer, Berlin Heidelberg New York, pp15–34Google Scholar
  127. 127.
    Discipio RG (1998) Late components. In: Rother K, Till GO, Hansch GM (eds) The complement system, 2nd edn.– Springer, Berlin Heidelberg New York, pp 50–68Google Scholar
  128. 128.
    Fernandez-Lopez S, Kim, HS, Choi EC, Delgado M, Granja JR, Khasanov A, Kraehenbuehl K, Long G, Weinberger DA, Wilcoxen KM, Ghadiri R (2001) Antibacterial agents based on the cyclic D,L-α-peptide architecture. Nature 412:452–455CrossRefPubMedGoogle Scholar
  129. 129.
    Yip CM, McLaurin J (2001) Amyloid β-peptide assembly: a critical step in fibrillogenesis and membrane disruption. Biophys J 80:1359–1371PubMedGoogle Scholar
  130. 130.
    Ji SR, Sui S-F (2002) Cholesterol is an important factor affecting the membrane insertion of β-amyloid peptide (Aβ1–40), which may potentially inhibit the fibril formation. J Biol Chem 277:6273–6279PubMedGoogle Scholar
  131. 131.
    Arispe N, Rojas E, Pollard HD (1993) Alzheimer's disease amyloid beta protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminium. Proc Natl Acad Sci USA 89:10940–10944Google Scholar
  132. 132.
    Mattson MP, Begley JG, Mark RJ, Furukawa, K (1997) Aβ25–35 induces rapid lysis of red blood cells: contrast with Aβ1–42 and examination of underlying mechanisms. Brain Res 771:147–153PubMedGoogle Scholar
  133. 133.
    Volles MJ, Lansbury PT (2002) Vesicle permeabilization by protofibrillar α-synuclein is sensitive to Parkinson's disease-linked mutations and occurs by a pore-like mechanism. Biochemistry 41:4595–4602PubMedGoogle Scholar
  134. 134.
    Kagan BL, Hirakura Y, Azimov R, Azimova R (2001) The channel hypothesis of Huntington's disease. Brain Res Bull 56:281–284PubMedGoogle Scholar
  135. 135.
    Monoi H, Futaki S, Kugimyia S, Minakata H, Yoshihara K (2000) Poly-L-glutamine forms cation channels: relevance to the pathogenesis of the polyglutamine diseases. Biophys J 78:2892–2899PubMedGoogle Scholar
  136. 136.
    Azimov R, Azimova R, Hirakura Y, Kagan BL (2001) Ion channels with different selectivity formed by transthyretin. Biophys J 80:129aGoogle Scholar
  137. 137.
    Wang L, Lashuel HA, Walz T, Colòn W (2002) Murine apolipoprotein serum amyloid A in solution forms a hexamer containing a central channel. Proc Natl Acad Sci USA 99:15947–15952PubMedGoogle Scholar
  138. 138.
    Shtilerman MD, Ding TT, Lansbury PT (2002) Molecular crowding accelerates fibrillization of alpha-synuclein: could an increase in the cytoplasmic protein concentration induce Parkinson's disease? Biochemistry 41:3855–3860PubMedGoogle Scholar
  139. 139.
    Pei JJ, Braak E, Braak H, Grundke-Iqbal Iqbal K, Winblad B, Cowburn RF (2002) Localization of active forms of c-Jun kinase (JNK) and p38 kinase in Alzheimer's disease brains at different stages of neurofibrillary degeneration. Alzheimers Dis 3:41–48Google Scholar
  140. 140.
    Savage MJ, Lin YG, Cialella JR, Flood DG, Scott RW (2002) Activation of c-Jun N-terminal kinase and p38 in an Alzheimer's disease model is associated with amyloid deposition. J Neurosci 22:3376–3385PubMedGoogle Scholar
  141. 141.
    Yang W, Dunlap JR, Andrews RB, Wetzel R (2002) Aggregated polyglutamine peptides delivered to nuclei are toxic to mammalian cells. Hum Mol Genet 11:2905–2917PubMedGoogle Scholar
  142. 142.
    Hegde RS, Tremblay P, Groth D, DeArmond SJ, Prusiner SB, Lingappa VR (1999) Transmissible and genetic prion diseases share a common pathway of neurodegeneration. Nature 402:822–826PubMedGoogle Scholar
  143. 143.
    International SNP Map Working Group (2001) A map of human sequence variation containing 1.4 million single nucleotide polymorphisms. Nature 409:928–933CrossRefPubMedGoogle Scholar
  144. 144.
    Perutz MF, Pope BJ, Owen D, Wanker EE, 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 β-peptide of amyloid plaques. Proc Natl Acad Sci USA 99:5596–5600PubMedGoogle Scholar
  145. 145.
    Checkoway H, Farin FM Costa-Mallen P, Kirchner SC, Costa LG (1998) Genetic polymorphisms in Parkinson's disease. Neurotoxicology 19:635–643PubMedGoogle Scholar
  146. 146.
    Dennis C (2003) Altered states. Nature 421:686–688PubMedGoogle Scholar
  147. 147.
    Stevens FJ, Argon Y (1999) Pathogenic light chains and the B-cell repertoire. Immunol Today 20:451–457PubMedGoogle Scholar
  148. 148.
    Dobson CM (2002) Getting out of shape. Nature 418:729–730PubMedGoogle Scholar
  149. 149.
    Wright PE, Dyson HJ (1999) Intrinsically unstructured proteins: reassessing the protein structure-function paradigm. J Mol Biol 293:321–331PubMedGoogle Scholar
  150. 150.
    Dedmon MM, Patel CN, Young GB, Pielak GJ (2002) FlgM gains structure in living cells. Proc Natl Acad Sci USA 99:12681–12684PubMedGoogle Scholar
  151. 151.
    Romero P, Obradovich Z, Kissinger C, Villafranca JE, Garner E, Guilliot S, Bunker AK (1998) Thousands of proteins likely to have long disordered regions. Pac Symp Biocomput 3:437–448Google Scholar
  152. 152.
    David DC, Layfield R, Serpell L, Narain Y, Groedert M, Spillantini MG (2002) Proteasomal degradation of tau protein. J Neurochem 83:176–185PubMedGoogle Scholar
  153. 153.
    Tofaris GK, Layfield R, Spillantini MG (2001) α-Synuclein metabolism and aggregation is linked to ubiquitin-independent degradation by the proteasome. FEBS Lett 509:22–26PubMedGoogle Scholar
  154. 154.
    Touitou R, Richardson J, Bose S, Nakanishi M, Rivett J, Allday MJ (2001) A degradation signal located in the C-terminus of p21WAF1/CIP1 is a binding site for the C8 alpha-subunit of the 20S proteasome. EMBO J 20:2367–2375PubMedGoogle Scholar
  155. 155.
    Kisselev AF, Akopian TN, Woo KM, Golberg AL (1999) The sizes of peptides generated from protein by mammalian 26 and 20 S proteasomes. J Biol Chem 274:3363–3371CrossRefPubMedGoogle Scholar
  156. 156.
    Cox CJ, Dutta K, Petri ET, Hwang WC, Lin Y, Pascal SM, Basavappa R (2002) The regions of securin and cyclin B proteins recognised by the ubiquitination machinery are natively unfolded. FEBS Lett 527:303–308PubMedGoogle Scholar
  157. 157.
    Bartek J, Lukas J (2001) Order from destruction. Science 294:66–67PubMedGoogle Scholar
  158. 158.
    Rüdiger S, Freund SMV, Veprintsev DB, Fersht AR (2002) CRINEPT-TROSY NMR reveals p53 core domain bound in an unfolded form to the chaperone Hsp90. Proc Natl Acad Sci USA 99:11085–11090PubMedGoogle Scholar
  159. 159.
    Wong KB, DeDeker BS, Freund SM, Proctor MR, Bycroft M, Fersht AR (1999) Hot-spot mutants of p53 core domain evince characteristic local structural changes. Proc Natl Acad Sci USA 96:8438–8442PubMedGoogle Scholar
  160. 160.
    Kirik D, Rosenblad C, Burger C, Lundberg C, Johansen TE, Muzyczka N, Mandel RJ, Bjorklund A (2002) Parkinson-like neurodegeneration induced by targeted overexpression of alpha-synuclein in the nigrostriatal system. J Neurosci 22:2780–2791PubMedGoogle Scholar
  161. 161.
    Trojanowski JQ, Ishihara T, Higuchi M, Yoshiyama Y, Hong M, Zhang B, Forman MS, Zukareva V, Lee VM (2002) Amyotrophic lateral sclerosis/parkinsonism dementia complex: transgenic mice provide insights into mechanisms underlying a common tauopathy in an ethnic minority on Guam. Exp Neurol 176:1–11PubMedGoogle Scholar
  162. 162.
    Fernando-Funez P, Nino-Rosales ML, de Gouyon B, She, WC, Luchak JM, Martinez P, Turiegano E, Benito J, Capovilla M, Skinner PJ, McCall A, Canal I, Orr HT, Zoghbi HY, Botas J (2000) Identification of genes that modify ataxin-1-induced neurodegeneration. Nature 408:101–106Google Scholar
  163. 163.
    Ma J, Wollmann R, Lindquist S (2002) Neurotoxicity and neurodegeneration when PrP accumulates in the cytosol. Science 298:1781–1785Google Scholar
  164. 164.
    Morgan CJ, Gelfrand M, Atreya C, Miranker A (2001) Kidney dialysis-associated amyloidosis: a molecular role for copper in fiber formation. J Mol Biol 309:339–345PubMedGoogle Scholar
  165. 165.
    Trinh CH, Smith DP, Kalverda AP, Phillips SEV, Radford S (2002) Crystal structure of monomeric human β-2-microglobulin reveals clues to its amyloidogenic properties. Proc Natl Acad Sci USA 99:9771–9776PubMedGoogle Scholar
  166. 166.
    Waelter S, Boeddrich A, Lurz R, Scherzinger E, Lueder G, Lebrach H, Wanker EE (2001) Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation. Mol Biol Cell 12:1393–1407PubMedGoogle Scholar
  167. 167.
    McNaught KSP, Mytilinieou C, JnoBaptiste R, Yabut J, Shashidharan P, Jenner P, Olanov CW (2002) Impairment of the ubiquitin-proteasome system causes dopaminergic cell death and inclusion body formation in ventral mesencephalic cultures. J Neurochem 81:301–306PubMedGoogle Scholar
  168. 168.
    Fonte V, Kapulkin V, Taft A, Fluet A, Friedman D, Link CD (2002) Interaction of intracellular β amyloid peptide with chaperone proteins. Proc Natl Acad Sci USA 99:9439–9444PubMedGoogle Scholar
  169. 169.
    Bonini NM (2002) Chaperoning brain degeneration. Proc Natl Acad Sci USA 99 Suppl 4:16407–16411CrossRefGoogle Scholar
  170. 170.
    Muchowski PJ, Schaffar G, Sittler A, Wanker EE, Hayer-Hartl MK, Hartl U (2000) Hsp70 and Hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils. Proc Natl Acad Sci USA 97:7841–7846CrossRefPubMedGoogle Scholar
  171. 171.
    Zoghbi HY, Botas J (2002) Mouse and fly models of neurodegeneration. Trends Genet 18:463–471PubMedGoogle Scholar
  172. 172.
    Auluck PK, Chan HYE, Trojanowski JQ, Lee VMY, Bonini NM (2002) Chaperone suppression of α-synuclein toxicity in a Drosophila model for Parkinson's disease. Science 295:865–868CrossRefPubMedGoogle Scholar
  173. 173.
    Bence NF, Sampat RM, Kopito RR (2001) Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292:1552–1555PubMedGoogle Scholar
  174. 174.
    Sakahira H, Breuer P, Hayer-Hartl MK, Hartl FU (2002) Molecular chaperones as modulators of polyglutamine protein aggregation and toxicity. Proc Natl Acad Sci USA 99 Suppl 4:16412–16418CrossRefGoogle Scholar
  175. 175.
    Chappie JP, Grayson CHardcastle AJ, Saliba RS, van der Spuy J, Cheetham ME (2001) Unfolding retinal dystrophies: a role for molecular chaperones? Trends Mol Med 7:414–421PubMedGoogle Scholar
  176. 176.
    Berlau J, Lorenz P, Beck R, Makovitzky J, Schlotzer-Schrehardt U, Thiesen HJ, Gauthoff R (2001) Analysis of aqueous humor proteins of eyes with and without pseudoexfoliation syndrome. Graefes Arch Clin Exp Ophthalmol 239:743–746PubMedGoogle Scholar
  177. 177.
    Bek T (2000) Ocular changes in heredo-oto-ophthalmo-encephalopathy. Br J Ophthalmol 84:1298–1302PubMedGoogle Scholar
  178. 178.
    Dul JL, Davis DP, Williamson EK, Satevens FJ, Argon, Y (2001) Hsp70 and antifibrillogenic peptides promote degradation and inhibit intracellular aggregation of amyloidogenic light chains. J Cell Biol 19:705–715CrossRefGoogle Scholar
  179. 179.
    Sandilands A, Hutcheson AM, Long HA, Prescott AR, Vrensen G, Löster J, Klopp N, Lutz RB, Graw J, Masaki S, Dobson CM, MacPhee CE, Quinlan RA (2002) Altered aggregation properties of mutant γ-crystallins cause inherited cataract. EMBO J 21:6005–6014PubMedGoogle Scholar
  180. 180.
    Kosinski-Collins M, King J (2003) In vitro unfolding, refolding, and polymerization of human γD crystallin, a protein involved in cataract formation. Protein Sci 12:480–490PubMedGoogle Scholar
  181. 181.
    Kopito RR, Sitia R (2000) Aggresomes and Russell bodies. EMBO Rep 1:225–231PubMedGoogle Scholar
  182. 182.
    Macario AJ L, de Macario EC (2002) Sick chaperones and ageing: a perspective. Ageing Res Rev 1:295–311PubMedGoogle Scholar
  183. 183.
    Yoo BC, Kim SH, Cairns N, Fountoulakis M, Lubec G (2001) Deranged expression of molecular chaperones in brains of patients with Alzheimer's disease. Biochem Biophys Res Commun 280:249–258PubMedGoogle Scholar
  184. 184.
    Layfield R, Alban A, Mayer RJ, Lowe J (2001) The ubiquitin protein catabolic disorders. Neuropathol Appl Neurobiol 27:171–179PubMedGoogle Scholar
  185. 185.
    Hartl FU, Hayer-Hartl M (2002) Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 295:1852–1858PubMedGoogle Scholar
  186. 186.
    Nardai G, Csermely P, Soti C (2002) Chaperone function and chaperone overload in the aged. A preliminary analysis. Exp Gerontol 37:1257–1262PubMedGoogle Scholar
  187. 187.
    Rutherford SL, Lindquist S (1998) Hsp90 as a capacitor for morphological evolution. Nature 396:336–342PubMedGoogle Scholar
  188. 188.
    Roberts SP, Fader ME (1999) Natural hyperthermia and expression of the heat shock protein Hsp70 affect developmental abnormalities in Drosophila melanogaster. Oecologia 121:323–329CrossRefGoogle Scholar
  189. 189.
    True HL, Lindquist S (2000) A yeast prion provides a mechanism for genetic variation and phenotypic diversity. Nature 407:477–483PubMedGoogle Scholar
  190. 190.
    Queiltsch CSangster TA, Lindquist S (2002) Hsp90 as a capacitor of phenotypic variation. Nature 417:618–624PubMedGoogle Scholar
  191. 191.
    Saliba RS, Munro PMG, Luthert PJ, Cheetham ME (2002) The cellular fate of mutant rhodopsin: quality control, degradation and aggresome formation. J Cell Sci 115:2907–2918PubMedGoogle Scholar
  192. 192.
    Ursini F, Davies KJ A, Maiorino M, Parasassi T, Sevanian A (2002) Atherosclerosis: another protein misfolding disease? Trends Mol Med 8:370–374PubMedGoogle Scholar
  193. 193.
    Wang J, Xu G, Borchelt DR (2002) High molecular weight complexes of mutant superoxide dismutase 1 age-dependent and tissue-specific accumulation. Neurobiol Dis 9:139–148PubMedGoogle Scholar
  194. 194.
    Gustaffson M, Thyberg J, Näslund J, Eliasson E, Johansson J (1999) Amyloid fibril formation by pulmonary surfactant protein C. FEBS Lett 464:136–142Google Scholar
  195. 195.
    Demirhan B, Bilezikci B, Kiyici, H, Boyacioglu S (2002) Globular amyloid deposits in the wall of the gastrointestinal tract: report of six cases. Amyloid 9:42–46PubMedGoogle Scholar
  196. 196.
    Csermely P (2001) Chaperone overload is a possible contributor to "civilization diseases." Trends Genet 17:701–704Google Scholar
  197. 197.
    Dodart JC, Bales KR, Bales KR, Paul SM (2003) Immunotherapy for Alzheimer's disease: will vaccination work? Trends Mol Med 9:85–87PubMedGoogle Scholar
  198. 198.
    Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297:353–356PubMedGoogle Scholar
  199. 199.
    Hammarström P, Wiseman RL, Powers ET, Kelly JW (2003) Prevention of transthyretin amyloid disease by changing protein misfolding energetics. Science 299:713–716PubMedGoogle Scholar
  200. 200.
    Harper JD, Wong SS, Lieber CM, Landsbury PT Jr (1999) Assembly of A beta amyloid protofibrils: an in vitro model for a possible early event in Alzheimer's disease. Biochemistry 38:8972–8980PubMedGoogle Scholar
  201. 201.
    Lashuel HA, Hartley D, Petre BM, Walz T, Lansbury PT Jr (2002) Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature 418:291CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  1. 1.Department of Biochemical SciencesUniversity of FlorenceFlorenceItaly
  2. 2.Department of ChemistryUniversity of CambridgeCambridgeUK

Personalised recommendations