Molecular Biotechnology

, Volume 31, Issue 2, pp 141–150 | Cite as

Protein misfolding, aggregation, and degradation in disease

  • Niels Gregersen
  • Lars Bolund
  • Peter BrossEmail author


Pathologies associated with protein misfolding have been observed in neurodegenerative diseases such as Alzheimer’s disease, metabolic diseases like phenylketonuria, and diseases affecting structural proteins like collagen or keratin. Misfolding of mutant proteins in these and many other diseases may result in premature degradation, formation of toxic aggregates, or incorporation of toxic conformations into structures. We review common traits of these diverse diseases under the unifying view of protein misfolding. The molecular pathogenesis is discussed in the context of protein quality control systems consisting of molecular chaperones and intracellular proteases that assist the folding and supervise the maintenance of the folded structure. Furthermore, genetic and environmental factors that may modify the severity of these diseases are underscored.

Index Entries

Conformational disease protein folding protein quality control protein misfolding protein aggregation protein aggregation diseases 


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  1. 1.
    Carrell, R. W. and Lomas, D. A. (1997) Conformational disease. Lancet 350, 134–138.PubMedCrossRefGoogle Scholar
  2. 2.
    Carrell, R. W. and Lomas, D. A. (2002) Alphal-antitrypsin deficiency—a model for conformational diseases. N. Engl. J. Med. 346, 45–53.PubMedCrossRefGoogle Scholar
  3. 3.
    Crowther, D. C. (2002) Familial conformational diseases and dementias. Hum. Mutat. 20, 1–14.PubMedCrossRefGoogle Scholar
  4. 4.
    Sorensen, C. B., Ladekjaer-Mikkelsen, A. S., Andresen, B. S., et al. (1999) Identification of novel and known mutations in the genes for keratin 5 and 14 in Danish patients with epidermolysis bullosa simplex: correlation between genotype and phenotype. J. Invest Dermatol. 112, 184–190.PubMedCrossRefGoogle Scholar
  5. 5.
    Baum, J. and Brodsky, B. (1999) folding of peptide models of collagen and misfolding in disease. Curr. Opin. Struct. Biol. 9, 122–128.PubMedCrossRefGoogle Scholar
  6. 6.
    Burch, M. and Blair, E. (1999) The inheritance of hypertrophic cardiomyopathy. Pediatr. Cardiol. 20, 313–316.PubMedCrossRefGoogle Scholar
  7. 7.
    Monti, P., Campomenosi, P., Ciribilli, Y., et al. (2002) Tumour p53 mutations exhibit promoter selective dominance over wild type p53. Oncogene 21, 1641–1648.PubMedCrossRefGoogle Scholar
  8. 8.
    Bross, P., Corydon, T. J., Andresen, B. S., Jørgensen, M. M., Bolund, L., and Gregersen, N. (1999) Protein misfolding and degradation in genetic diseases. Hum. Mutat. 14, 186–198.PubMedCrossRefGoogle Scholar
  9. 9.
    Gregersen, N., Bross, P., Andresen, B. S., Pedersen, C. B., Corydon, T. J., and Bolund, L. (2001) The role of chaperone-assisted folding and quality control in inborn errors of metabolism: protein folding disorders. J. Inherit. Metab. Dis. 24, 189–212.PubMedCrossRefGoogle Scholar
  10. 10.
    Waters, P. J. (2001) Degradation of mutant proteins, underlying “loss of function” phenotypes, plays a major role in genetic disease. Curr. Issues Mol. Biol. 3, 57–65.PubMedGoogle Scholar
  11. 11.
    Riordan, J. R. (1999) Cystic fibrosis as a disease of misprocessing of the cystic fibrosis transmembrane conductance regulator glycoprotein. Am. J. Hum. Genet. 64, 1499–1504.PubMedCrossRefGoogle Scholar
  12. 12.
    Waters, P. J., Parniak, M. A., Akerman, B. R., and Scriver, C. R. (2000) Characterization of phenylketonuria missense substitutions, distant from the phenylalanine hydroxylase active site, illustrates a paradigm for mechanism and potential modulation of phenotype. Mol. Genet. Metab. 69, 101–110.PubMedCrossRefGoogle Scholar
  13. 13.
    Waters, P. J. (2003) How PAH gene mutations cause hyper-phenylalaninemia and why mechanism matters: insights from in vitro expression. Hum. Mutat. 21, 357–369.PubMedCrossRefGoogle Scholar
  14. 14.
    Perlmutter, D. H. (1999) Misfolded proteins in the endoplasmic reticulum. Lab. Invest. 79, 623–638.PubMedGoogle Scholar
  15. 15.
    Gregersen, N., Andresen, B. S., Corydon, M. J., et al. (2001) Mutation analysis in mitochondrial fatty acid oxidation defects: exemplified by acyl-CoA dehydrogenase deficiencies, with special focus on genotype-phenotype relationship. Hum. Mutat. 18, 169–189.PubMedCrossRefGoogle Scholar
  16. 16.
    Gregersen, N., Bross, P., and Andresen, B. S. (2004) Genetic defects in fatty acid beta-oxidation and acyl-CoA dehydrogenases. Eur. J. Biochem. 271, 470–482.PubMedCrossRefGoogle Scholar
  17. 17.
    Bross, P. and Gregersen, N. (2003) Protein Misfolding and Disease—Principles and Protocols. Humana, Totowa, NJ.Google Scholar
  18. 18.
    Uversky, V. N. (2002) Natively unfolded proteins: a point where biology waits for physics. Protein Sci. 11, 739–756.PubMedCrossRefGoogle Scholar
  19. 19.
    Barral, J. M., Broadley, S. A., Schaffar, G., and Hartl, F. U. (2004) Roles of molecular chaperones in protein misfolding diseases. Semin. Cell Dev. Biol. 15, 17–29.PubMedCrossRefGoogle Scholar
  20. 20.
    Gregersen, N., Bross, P., and Jørgensen, M. M. Chapter 13.1: Protein folding and misfolding: The role of cellular protein quality control systems in inherited disorders. In: MMBID-ONLINE (Scriver, C. R., Beaudet, A. L., Valle, D., Sly, W. S., Vogelstein, B., Childs, B., and Kinzler, K. W., eds.), McGraw-Hill, New York, URL: Scholar
  21. 21.
    Cooper, D. N. and Krawczak, M. (1993) Human Gene Mutation. Bios Scientific Publishers, Ltd., Oxford, UK.Google Scholar
  22. 22.
    Krawczak, M., Ball, E. V., Fenton, I., et al. (2000) Human gene mutation database—a biomedical information and research resource. Hum. Mutat. 15, 45–51.PubMedCrossRefGoogle Scholar
  23. 23.
    Cartegni, L., Chew, S. L., and Krainer, A. R. (2002) Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat. Rev. Genet. 3, 285–298.PubMedCrossRefGoogle Scholar
  24. 24.
    Milewski, M. I., Mickle, J. E., Forrest, J. K., Stanton, B. A., and Cutting, G. R. (2002) Aggregation of misfolded proteins can be a selective process dependent upon peptide composition. J. Biol. Chem. 277, 34462–34470.PubMedCrossRefGoogle Scholar
  25. 25.
    Johnston, J. A., Ward, C. L., and Kopito, R. R. (1998) Aggresomes: a cellular response to misfolded proteins. J. Cell Biol. 143, 1883–1898.PubMedCrossRefGoogle Scholar
  26. 26.
    Pedersen, C. B., Bross, P., Winter, V. S., et al. (2003) Misfolding, Degradation, and aggregation of variant proteins: the molecular pathogenesis of short chain acyl-CoA dehydrogenase (SCAD) deficiency. J. Biol. Chem. 278, 47449–47458.PubMedCrossRefGoogle Scholar
  27. 27.
    Vladutiu, G. D. (1999) Biochemical and molecular correlations in carnitine palmitoyltransferase II deficiency. Muscle Nerve 22, 949–951.PubMedCrossRefGoogle Scholar
  28. 28.
    Sorensen, C. B., Ladekjaer-Mikkelsen, A. S., Andresen, B. S., et al. (1999) Identification of novel and known mutations in the genes for keratin 5 and 14 in Danish patients with epidermolysis bullosa simplex: correlation between genotype and phenotype. J. Invest Dermatol. 112, 184–190.PubMedCrossRefGoogle Scholar
  29. 29.
    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, 133–145.PubMedCrossRefGoogle Scholar
  30. 30.
    Wu, Y., Whitman, I., Molmenti, E., Moore, K., Hippenmeyer, P., and Perlmutter, D. H. (1994) A lag in intracellular degradation of mutant alpha 1-antitrypsin correlates with the liver disease phenotype in homozygous PiZZ alpha 1-antitrypsin deficiency. Proc. Natl. Acad. Sci. USA 91, 9014–9018.PubMedCrossRefGoogle Scholar
  31. 31.
    Lomas, D. A., Evans, D. L., Finch, J. T., and Carrell, R. W. (1992) The mechanism of Z alpha 1-antitrypsin accumulation in the liver. Nature 357, 605–607.PubMedCrossRefGoogle Scholar
  32. 32.
    Perutz, M. F. (1999) Glutamine repeats and neurodegenerative diseases: molecular aspects. Trends Biochem. Sci. 24, 58–63.PubMedCrossRefGoogle Scholar
  33. 33.
    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.PubMedGoogle Scholar
  34. 34.
    Taylor, J. P., Hardy, J., and Fischbeck, K. H. (2002) Toxic proteins in neurodegenerative disease. Science 296, 1991–1995.PubMedCrossRefGoogle Scholar
  35. 35.
    Zoghbi, H. Y. and Botas, J. (2002) Mouse and fly models of neurodegeneration. Trends Genet. 18, 463–471.PubMedCrossRefGoogle Scholar
  36. 36.
    Chiti, F., Taddei, N., Baroni, F., et al. (2002) Kinetic partitioning of protein folding and aggregation. Nat. Struct. Biol. 9, 137–143.PubMedCrossRefGoogle Scholar
  37. 37.
    Soto, C. (2001) Protein misfolding and disease; protein refolding and therapy. FEBS Lett. 498, 204–207.PubMedCrossRefGoogle Scholar
  38. 38.
    Bucciantini, M., Giannoni, E., Chiti, F., et al. (2002) Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature 416, 507–511.PubMedCrossRefGoogle Scholar
  39. 39.
    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, 535–539.PubMedCrossRefGoogle Scholar
  40. 40.
    Kayed, R., Head, E., Thompson, J. L., et al. (2003) Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300, 486–489.PubMedCrossRefGoogle Scholar
  41. 41.
    Teckman, J. H. and Perlmutter, D. H. (2000) Retention of mutant alpha(1)-antitrypsin Z in endoplasmic reticulum is associated with an autophagic response. Am. J. Physiol Gastrointest. Liver Physiol. 279, G961-G974.PubMedGoogle Scholar
  42. 42.
    Earl, R. T., Mangiapane, E. H., Billett, E. E., and Mayer, R. J. (1987) A putative protein-sequestration site involving intermediate filaments for protein degradation by autophagy. Studies with transplanted Sendai-viral envelope proteins in HTC cells. Biochem. J. 241, 809–815.PubMedGoogle Scholar
  43. 43.
    Weihofen, A., Binns, K., Lemberg, M. K., Ashman, K., and Martoglio, B. (2002) Identification of signal peptide peptidase, a presenilin-type aspartic protease. Science 296, 2215–2218.PubMedCrossRefGoogle Scholar
  44. 44.
    Yang, Y., Turner, R. S., and Gaut, J. R. (1998) The chaperone BiP/GRP78 binds to amyloid precursor protein and decreases Abeta40 and Abeta42 secretion. J. Biol. Chem. 273, 25552–25555.PubMedCrossRefGoogle Scholar
  45. 45.
    Weber, A. J., Soong, G., Bryan, R., Saba, S., and Prince, A. (2001) Activation of NF-kappaB in airway epithelial cells is dependent on CFTR trafficking and Cl- channel function. Am. J. Physiol Lung Cell Mol. Physiol. 281, L71-L78.PubMedGoogle Scholar
  46. 46.
    Zhao, Q., Wang, J., Levichkin, I. V., Stasinopoulos, S., Ryan, M. T., and Hoogenraad, N. J. (2002) A mitochondrial specific stress response in mammalian cells. EMBO J. 21, 4411–4419.PubMedCrossRefGoogle Scholar
  47. 47.
    Uversky, V. N., Lee, H. J., Li, J., Fink, A. L., and Lee, S. J. (2001) Stabilization of partially folded conformation during alpha-synuclein oligomerization in both purified and cytosolic preparations. J. Biol. Chem. 276, 43495–43498.PubMedCrossRefGoogle Scholar
  48. 48.
    Beal, M. F. (2000) Energetics in the pathogenesis of neurodegenerative diseases. Trends Neurosci. 23, 298–304.PubMedCrossRefGoogle Scholar
  49. 49.
    Butterfield, D. A. and Kanski, J. (2001) Brain protein oxidation in age-related neurodegenerative disorders that are associated with aggregated proteins. Mech. Ageing Dev. 122, 945–962.PubMedCrossRefGoogle Scholar
  50. 50.
    Bence, N. F., Sampat, R. M., and Kopito, R. R. (2001) Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292, 1552–1555.PubMedCrossRefGoogle Scholar
  51. 51.
    Imaizumi, K., Miyoshi, K., Katayama, T., et al. (2001) The unfolded protein response and Alzheimer’s disease. Biochim. Biophys. Acta 1536, 85–96.PubMedGoogle Scholar
  52. 52.
    Martindale, J. L. and Holbrook, N. J. (2002) Cellular response to oxidative stress: signaling for suicide and survival. J. Cell Physiol. 192, 1–15.PubMedCrossRefGoogle Scholar
  53. 53.
    Hughes, R. E. (2002) Polyglutamine disease: acetyltransferases awry. Curr. Biol. 12, R141-R143.PubMedCrossRefGoogle Scholar
  54. 54.
    Schaffar, G., Breuer, P., Boteva, R., et al. (2004) Cellular toxicity of polyglutamine expansion proteins: mechanism of transcription factor deactivation. Mol. Cell 15, 95–105.PubMedCrossRefGoogle Scholar
  55. 55.
    Dukan, S., Farewell, A., Ballesteros, M., Taddei, F., Radman, M., and Nystrom, T. (2000) Protein oxidation in response to increased transcriptional or translational errors. Proc. Natl. Acad. Sci. USA 97, 5746–5749.PubMedCrossRefGoogle Scholar
  56. 56.
    Gamez, A., Perez, B., Ugarte, M., and Desviat, L. R. (2000) Expression analysis of phenylketonuria mutations. Effect on folding and stability of the phenylalanine hydroxylase protein. J. Biol. Chem. 275, 29,737–29,742.CrossRefGoogle Scholar
  57. 57.
    Pind, S., Riordan, J. R., and Williams, D. B. (1994) Participation of the endoplasmic reticulum chaperone calnexin (P88, Ip90) in the biogenesis of the cystic fibrosis transmembrane conductance regulator. J. Biol. Chem. 269, 12784–12788.PubMedGoogle Scholar
  58. 58.
    Qu, D. F., Teckman, J. H., Omura, S., and Perlmutter, D. H. (1996) Degradation of a mutant secretory protein, alpha(1)- antitrypsin Z, in the endoplasmic reticulum requires proteasome activity. J. Biol. Chem. 271, 22791–22795.PubMedCrossRefGoogle Scholar
  59. 59.
    Soti, C. and Csermely, P. (2000) Molecular chaperones and the aging process. Biogerontology 1, 225–233.PubMedCrossRefGoogle Scholar
  60. 60.
    Macario, A. J. and Conway de, M. E. (2002) Sick chaperones and ageing: a perspective. Ageing Res. Rev. 1, 295–311.PubMedCrossRefGoogle Scholar
  61. 61.
    Slavotinek, A. M. and Biesecker, L. G. (2001) Unfolding the role of chaperones and chaperonins in human disease. Trends Genet. 17, 528–535.PubMedCrossRefGoogle Scholar
  62. 62.
    Benndorf, R. and Welsh, M. J. (2004) Shocking degeneration. Nat. Genet. 36, 547–548.PubMedCrossRefGoogle Scholar
  63. 63.
    Casari, G., De Fusco, M., Ciarmatori, S., et al. (1998) Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell 93, 973–983.PubMedCrossRefGoogle Scholar
  64. 64.
    Hazan, J., Fonknechten, N., Mavel, D., et al. (1999) Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia. Nat. Genet. 23, 296–303.PubMedCrossRefGoogle Scholar
  65. 65.
    Hansen, J. J., Dürr, A., Cournu-Rebeix, I., et al. (2002) Hereditary spastic paraplegia SPG13 is associated with a mutation in the gene encoding the mitochondrial chaperonin Hsp60. Am. J. Hum. Genet. 70, 1328–1332.PubMedCrossRefGoogle Scholar
  66. 66.
    Atorino, L., Silvestri, L., Koppen, M., et al. (2003) Loss of m-AAA protease in mitochondria causes complex I deficiency and increased sensitivity to oxidative stress in hereditary spastic paraplegia. J. Cell Biol. 163, 777–787.PubMedCrossRefGoogle Scholar
  67. 67.
    Litt, M., Kramer, P., LaMorticella, D. M., Murphey, W., Lovrien, E. W., and Weleber, R. G. (1998) Autosomal dominant mutation of congenital cataract associated with a missense mutation in the alpha-crystallin gene CRYAA. Hum. Mol. Genet. 7, 471–474.PubMedCrossRefGoogle Scholar
  68. 68.
    Noor, R., Mittal, S., and Iqbal, J. (2002) Superoxide dismutase—applications and relevance to human diseases. Med. Sci. Monit. 8, RA210-RA215.PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2005

Authors and Affiliations

  1. 1.Research Unit for Molecular Medicine, Institute for Clinical MedicineAarhus University Hospital SKSÅrhus NDenmark
  2. 2.Department of Human GeneticsAarhus University Hospital SKSÅrhus NDenmark

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