Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-5f56664f6-p8hl4 Total loading time: 0 Render date: 2025-05-07T18:21:08.832Z Has data issue: false hasContentIssue false

7 - Diseases of protein misfolding

Published online by Cambridge University Press:  17 August 2009

By
Christopher M. Dobson
Edited by
Alan Wright  and
Nicholas Hastie
Alan Wright
Affiliation:
MRC Human Genetics Unit, Edinburgh
Nicholas Hastie
Affiliation:
MRC Human Genetics Unit, Edinburgh
Get access

Summary

Introduction

The ability of even the most complex protein molecules to fold to their biologically functional states is perhaps the most fundamental example of biological self-assembly, one of the defining characteristics of living systems (Vendruscolo et al., 2003). The process of protein folding in the cellular environment can, in principle, begin whilst the nascent chain is still attached to the ribosome, and there is clear evidence that some proteins do fold at least partially in such a co-translational manner (Hardesty and Kramer, 2001). Other proteins are known to undergo the major part of their folding only after release from the ribosome, whilst yet others fold in specific cellular compartments such as the endoplasmic reticulum (ER) or mitochondria following translocation through membranes (Hartl and Hayer-Hartl, 2002). Although the fundamental principles underlying the mechanism of folding are unlikely to differ in any significant manner from those elucidated from in vitro studies, many details of the way in which individual proteins fold will undoubtedly depend on the environment in which they are located. In particular, as incompletely folded chains inevitably expose to the outside world many regions of the polypeptide molecule that are buried in the native state, such species are prone to inappropriate interactions with other molecules within the complex and crowded cellular environment. Such interactions can result both in the disruption of normal cellular processes and in self-association or aggregation.

Type
Chapter
Information
Genes and Common Diseases
Genetics in Modern Medicine
 , pp. 113 - 131
Publisher: Cambridge University Press
Print publication year: 2007

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Book purchase

Temporarily unavailable

References

Bence, N. F., Sampat, R. M. and Kopito, R. R. (2001). Impairment of the ubiquitin-proteasome system by protein aggregation. Science, 292, 1552–5.CrossRefGoogle ScholarPubMed
Bitan, G., Kirkitadze, M. D., Lomakin, A.et al. (2003). Amyloid beta-protein (Abeta) assembly: Abeta 40 and Abeta 42 oligomerize through distinct pathways. Proc Natl Acad Sci USA, 100, 330–5.CrossRefGoogle ScholarPubMed
Booth, D. R., Sunde, M., Bellotti, V.et al. (1997). Instability, unfolding and aggregation of human lysozyme variants underlying amyloid fibrillogenesis. Nature, 385, 787–93.CrossRefGoogle ScholarPubMed
Bouchard, M., Zurdo, J., Nettleton, E. J., Dobson, C. M. and Robinson, C. V. (2000). Formation of insulin amyloid fibrils followed by FTIR simultaneously with CD and electron microscopy. Protein Sci, 9, 1960–7.CrossRefGoogle ScholarPubMed
Bucciantini, M., Giannoni, E., Chiti, F.et al. (2002). Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature, 416, 507–11.CrossRefGoogle ScholarPubMed
Capaldi, A. P., Kleanthous, C. and Radford, S. E. (2002). Im7 folding mechanism: misfolding on a path to the native state. Nat Struct Biol, 9, 209–16.Google ScholarPubMed
Carrell, R. W. and Lomas, D. A. (2002). Alpha1-antitrypsin deficiency–a model for conformational diseases. N Engl J Med, 346, 45–53.CrossRefGoogle ScholarPubMed
Caughey, B. and Lansbury, P. T. (2003). Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu Rev Neurosci, 26, 267–98.CrossRefGoogle ScholarPubMed
Chamberlain, A. K., MacPhee, C. E., Zurdo, J.et al. (2000). Ultrastructural organization of amyloid fibrils by atomic force microscopy. Biophys J, 79, 3282–93.CrossRefGoogle ScholarPubMed
Chien, P., DePace, A. H., Collins, S. R. and Weissman, J. S. (2003). Generation of prion transmission barriers by mutational control of amyloid conformations. Nature, 424, 948–51.CrossRefGoogle ScholarPubMed
Chiti, F., Stefani, M., Taddei, N., Ramponi, G. and Dobson, C. M. (2003). Rationalization of the effects of mutations on peptide and protein aggregation rates. Nature, 424, 805–8.CrossRefGoogle ScholarPubMed
Chiti, F., Taddei, N., Baroni, F.et al. (2002). Kinetic partitioning of protein folding and aggregation. Nat Struct Biol, 9, 137–43.CrossRefGoogle ScholarPubMed
Chiti, F., Webster, P., Taddei, N.et al. (1999). Designing conditions for in vitro formation of amyloid protofilaments and fibrils. Proc Natl Acad Sci USA, 96, 3590–4.CrossRefGoogle ScholarPubMed
Csermely, P. (2001). Chaperone overload is a possible contributor to ‘civilization diseases’. Trends Genet, 17, 701–4.CrossRefGoogle ScholarPubMed
Dobson, C. M. (1999 a). How do we explore the energy landscape for folding? In Fraunfelder, H., Deisenhofer, J. and Wolynes, P. G. ed., Simplicity and Complexity in Proteins and Nucleic Acids, pp. 15–37. Berlin: Dahlem University Press.Google Scholar
Dobson, C. M. (1999 b). Protein misfolding, evolution and disease. Trends Biochem Sci, 24, 329–32.CrossRefGoogle ScholarPubMed
Dobson, C. M. (2001). The structural basis of protein folding and its links with human disease. Philos Trans R Soc Lond B Biol Sci, 356, 133–45.CrossRefGoogle ScholarPubMed
Dobson, C. M. (2002). Getting out of shape. Nature, 418, 729–30.CrossRefGoogle ScholarPubMed
Dobson, C. M. (2003 a). Protein folding and disease: a view from the first Horizon Symposium. Nat Rev Drug Discov, 2, 154–60.CrossRefGoogle ScholarPubMed
Dobson, C. M. (2003 b). Protein folding and misfolding. Nature, 426, 884–90.CrossRefGoogle ScholarPubMed
Dobson, C. M. (2004). Protein chemistry. In the footsteps of alchemists. Science, 304, 1259–62.CrossRefGoogle ScholarPubMed
Dobson, C. M. and Karplus, M. (1999). The fundamentals of protein folding: bringing together theory and experiment. Curr Opin Struct Biol, 9, 92–101.CrossRefGoogle ScholarPubMed
Dumoulin, M., Last, A. M., Desmyter, A.et al. (2003). A camelid antibody fragment inhibits the formation of amyloid fibrils by human lysozyme. Nature, 424, 783–8.CrossRefGoogle ScholarPubMed
Fandrich, M. and Dobson, C. M. (2002). The behaviour of polyamino acids reveals an inverse side chain effect in amyloid structure formation. Embo J, 21, 5682–90.CrossRefGoogle ScholarPubMed
Fandrich, M., Fletcher, M. A. and Dobson, C. M. (2001). Amyloid fibrils from muscle myoglobin. Nature, 410, 165–6.CrossRefGoogle ScholarPubMed
Gejyo, F., Homma, N., Suzuki, Y. and Arakawa, M. (1986). Serum levels of beta 2-microglobulin as a new form of amyloid protein in patients undergoing long-term hemodialysis. N Engl J Med, 314, 585–6.Google ScholarPubMed
Gething, M. J. and Sambrook, J. (1992). Protein folding in the cell. Nature, 355, 33–45.CrossRefGoogle Scholar
Hammarstrom, P., Wiseman, R. L., Powers, E. T. and Kelly, J. W. (2003). Prevention of transthyretin amyloid disease by changing protein misfolding energetics. Science, 299, 713–16.CrossRefGoogle ScholarPubMed
Hammond, C. and Helenius, A. (1995). Quality control in the secretory pathway. Curr Opin Cell Biol, 7, 523–9.CrossRefGoogle ScholarPubMed
Hardesty, B. and Kramer, G. (2001). Folding of a nascent peptide on the ribosome. Prog Nucleic Acid Res Mol Biol, 66, 41–66.CrossRefGoogle ScholarPubMed
Harper, J. D. and Lansbury, P. T. Jr. (1997). Models of amyloid seeding in Alzheimer's disease and scrapie: mechanistic truths and physiological consequences of the time-dependent solubility of amyloid proteins. Annu Rev Biochem, 66, 385–407.CrossRefGoogle ScholarPubMed
Hartl, F. U. and Hayer-Hartl, M. (2002). Molecular chaperones in the cytosol: from nascent chain to folded protein. Science, 295, 1852–8.CrossRefGoogle ScholarPubMed
Hartl, U. (2000). In Pain, R. H. (ed.), Mechanisms of protein folding, Oxford: Oxford University Press.Google Scholar
Hoppener, J. W., Nieuwenhuis, M. G., Vroom, T. M., Ahren, B. and Lips, C. J. (2002). Role of islet amyloid in type 2 diabetes mellitus: consequence or cause?Mol Cell Endocrinol, 197, 205–12.CrossRefGoogle ScholarPubMed
Hore, P. J., Winder, S. L., Roberts, C. H. and Dobson, C. M. (1997). Stopped-flow photo-CIDNP observation of protein folding. J Am Chem Soc, 119, 5049–50.CrossRef
Horwich, A. (2002). Protein aggregation in disease: a role for folding intermediates forming specific multimeric interactions. J Clin Invest, 110, 1221–32.CrossRefGoogle ScholarPubMed
Jimenez, J. L., Guijarro, J. I., Orlova, E.et al. (1999). Cryo-electron microscopy structure of an SH3 amyloid fibril and model of the molecular packing. Embo J, 18, 815–21.CrossRefGoogle ScholarPubMed
Jimenez, J. L., Nettleton, E. J., Bouchard, M.et al. (2002). The protofilament structure of insulin amyloid fibrils. Proc Natl Acad Sci USA, 99, 9196–201.CrossRefGoogle ScholarPubMed
Kaufman, R. J., Scheuner, D., Schroder, M.et al. (2002). The unfolded protein response in nutrient sensing and differentiation. Nat Rev Mol Cell Biol, 3, 411–21.CrossRefGoogle Scholar
Kayed, R., Head, E., Thompson, J. L.et al. (2003). Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science, 300, 486–9.CrossRefGoogle ScholarPubMed
Kelly, J. W. (1998). The alternative conformations of amyloidogenic proteins and their multi-step assembly pathways. Curr Opin Struct Biol, 8, 101–6.CrossRefGoogle ScholarPubMed
Koo, E. H., Lansbury, P. T. Jr. and Kelly, J. W. (1999). Amyloid diseases: abnormal protein aggregation in neurodegeneration. Proc Natl Acad Sci USA, 96, 9989–90.CrossRefGoogle ScholarPubMed
Lashuel, H. A., Hartley, D., Petre, B. M., Walz, T. and Lansbury, P. T. Jr. (2002). Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature, 418, 291.CrossRefGoogle ScholarPubMed
Lopez De La Paz, M., Goldie, K., Zurdo, J.et al. (2002). De novo designed peptide-based amyloid fibrils. Proc Natl Acad Sci USA, 99, 16052–7.CrossRefGoogle ScholarPubMed
Macario, A. J. and Conway de Macario, E. (2002). Sick chaperones and ageing: a perspective. Ageing Res Rev, 1, 295–311.CrossRefGoogle ScholarPubMed
Matouschek, A. (2003). Protein unfolding–an important process in vivo?Curr Opin Struct Biol, 13, 98–109.CrossRefGoogle ScholarPubMed
May, B. C., Fafarman, A. T., Hong, S. B.et al. (2003). Potent inhibition of scrapie prion replication in cultured cells by bis-acridines. Proc Natl Acad Sci USA, 100, 3416–21.CrossRefGoogle ScholarPubMed
Muchowski, P. J., Schaffar, G., Sittler, A.et al. (2000). Hsp70 and hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils. Proc Natl Acad Sci USA, 97, 7841–6.CrossRefGoogle ScholarPubMed
Nettleton, E. J., Tito, P., Sunde, M.et al. (2000). Characterization of the oligomeric states of insulin in self-assembly and amyloid fibril formation by mass spectrometry. Biophys J, 79, 1053–65.CrossRefGoogle ScholarPubMed
Nicoll, J. A., Wilkinson, D., Holmes, C.et al. (2003). Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med, 9, 448–52.CrossRefGoogle ScholarPubMed
Oeppen, J. and Vaupel, J. W. (2002). Demography. Broken limits to life expectancy. Science, 296, 1029–31.CrossRefGoogle ScholarPubMed
Padrick, S. B. and Miranker, A. D. (2002). Islet amyloid: phase partitioning and secondary nucleation are central to the mechanism of fibrillogenesis. Biochemistry, 41, 4694–703.CrossRefGoogle ScholarPubMed
Parsell, D. A., Kowal, A. S., Singer, M. A. and Lindquist, S. (1994). Protein disaggregation mediated by heat-shock protein Hsp104. Nature, 372, 475–8.CrossRefGoogle ScholarPubMed
Pelham, H. R. (1968). Speculations on the functions of the major heat shock and glucose-regulated proteins. Cell, 46, 959–61.CrossRefGoogle Scholar
Pepys, M. B. (1995). In Weatherall, D. J., Ledingham, J. G. and Warrel, D. A. (eds.), Oxford textbook of medicine, pp. 1512–24. Oxford: Oxford University Press.Google Scholar
Pepys, M. B., Herbert, J., Hutchinson, W. L.et al. (2002). Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis. Nature, 417, 254–9.CrossRefGoogle ScholarPubMed
Perutz, M. F. and Windle, A. H. (2001). Cause of neural death in neurodegenerative diseases attributable to expansion of glutamine repeats. Nature, 412, 143–4.CrossRefGoogle ScholarPubMed
Polverino de Laureto, P., Taddei, N., Frare, E.et al. (2003). Protein aggregation and amyloid fibril formation by an SH3 domain probed by limited proteolysis. J Mol Biol, 334, 129–41.CrossRefGoogle ScholarPubMed
Powell, K. and Zeitlin, P. L. (2002). Therapeutic approaches to repair defects in deltaF508 CFTR folding and cellular targeting. Adv Drug Deliv Rev, 54, 1395–408.CrossRefGoogle ScholarPubMed
Prusiner, S. B. (1997). Prion diseases and the BSE crisis. Science, 278, 245–51.CrossRefGoogle ScholarPubMed
Radford, S. E. and Dobson, C. M. (1999). From computer simulations to human disease: emerging themes in protein folding. Cell, 97, 291–8.CrossRefGoogle ScholarPubMed
Ramirez-Alvarado, M., Merkel, J. S. and 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, 8979–84.CrossRefGoogle ScholarPubMed
Schenk, D. (2002). Amyloid-beta immunotherapy for Alzheimer's disease: the end of the beginning. Nat Rev Neurosci, 3, 824–8.CrossRefGoogle ScholarPubMed
Schlunegger, M. P., Bennett, M. J. and Eisenberg, D. (1997). Oligomer formation by 3D domain swapping: a model for protein assembly and misassembly. Adv Protein Chem, 50, 61–122.CrossRefGoogle ScholarPubMed
Schubert, U., Anton, L. C., Gibbs, J.et al. (2000). Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature, 404, 770–4.CrossRefGoogle ScholarPubMed
Selkoe, D. J. (2003). Folding proteins in fatal ways. Nature, 426, 900–4.CrossRefGoogle ScholarPubMed
Serpell, L. C., Blake, C. C. and Fraser, P. E. (2000). Molecular structure of a fibrillar Alzheimer's A beta fragment. Biochemistry, 39, 13269–75.CrossRefGoogle ScholarPubMed
Sherman, M. Y. and Goldberg, A. L. (2001). Cellular defenses against unfolded proteins: a cell biologist thinks about neurodegenerative diseases. Neuron, 29, 15–32.CrossRefGoogle ScholarPubMed
Spillantini, M. G., Schmidt, M. L., Lee, V. M.et al. (1997). Alpha-synuclein in Lewy bodies. Nature, 388, 839–40.CrossRefGoogle ScholarPubMed
Stefani, M. and Dobson, C. M. (2003). Protein aggregation and aggregate toxicity: new insights into protein folding, misfolding diseases and biological evolution. J Mol Med, 81, 678–99.CrossRefGoogle ScholarPubMed
Sunde, M. and Blake, C. (1997). The structure of amyloid fibrils by electron microscopy and X-ray diffraction. Adv Protein Chem, 50, 123–59.CrossRefGoogle ScholarPubMed
Svensson, M., Sabharwal, H., Hakansson, A.et al. (1999). Molecular characterization of alpha-lactalbumin folding variants that induce apoptosis in tumor cells. J Biol Chem, 274, 6388–96.CrossRefGoogle ScholarPubMed
Thomas, P. J., Qu, B. H. and Pedersen, P. L. (1995). Defective protein folding as a basis of human disease. Trends Biochem Sci, 20, 456–9.CrossRefGoogle ScholarPubMed
Vassar, R. (2002). Beta-secretase (BACE) as a drug target for Alzheimer's disease. Adv Drug Deliv Rev, 54, 1589–602.CrossRefGoogle ScholarPubMed
Vendruscolo, M., Zurdo, J., MacPhee, C. E. and Dobson, C. M. (2003). Protein folding and misfolding: a paradigm of self-assembly and regulation in complex biological systems. Philos Transact A Math Phys Eng Sci, 361, 1205–22.CrossRefGoogle ScholarPubMed
Vogtherr, M., Grimme, S., Elshorst, B.et al. (2003). Antimalarial drug quinacrine binds to C-terminal helix of cellular prion protein. J Med Chem, 46, 3563–4.CrossRefGoogle ScholarPubMed
Walsh, D. M., Klyubin, I., Fadeeva, J. V.et al. (2002). Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature, 416, 535–9.CrossRefGoogle ScholarPubMed
Wille, H., Michelitsch, M. D., Guenebaut, V.et al. (2002). Structural studies of the scrapie prion protein by electron crystallography. Proc Natl Acad Sci USA, 99, 3563–8.CrossRefGoogle ScholarPubMed
Wilson, M. R. and Easterbrook-Smith, S. B. (2000). Clusterin is a secreted mammalian chaperone. Trends Biochem Sci, 25, 95–8.CrossRefGoogle ScholarPubMed
Wolfe, M. S. (2002). Secretase as a target for Alzheimer's disease. Curr Top Med Chem, 2, 371–83.CrossRefGoogle ScholarPubMed

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×