Protein Folding Diseases

  • Engelbert Buxbaum


Many important diseases including morbusAlzheimer, Prion diseases, type II diabetes, or some cancers involve protein misfolding. In all these diseases, called amyloidoses, intrinsically disordered proteins fold into \(\upbeta\)-helices. One misfolded protein molecule auto-catalytically converts other protein molecules, leading to aggregation. Intracellular aggregates are called inclusion bodies, and extracellular aggregates fibrils. It is unclear whether the aggregates themselves are the cause of the cell destruction that leads to disease, or whether the damage is caused by soluble intermediates. Thus, although all these diseases are caused by misfolding of different proteins in different cells, the underlying pathomechanism is identical. This raises hope that one day they may be treated in a similar manner.


Amyotrophic Lateral Sclerosis Alzheimer Disease Familial Mediterranean Fever Amyloid Precursor Protein Prion Protein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    A. Alzheimer, Über eine eigenartige Erkrankung der Hirnrinde. Allg. Zeitschr. Psychiat. Psychisch-gerichtliche Med. 64, 146–148 (1907). doi: 10.1002/ca.980080612. URL
  2. 2.
    T. Alper, The exceptionally small size of the Scrapie agent. Biochem. Biophys. Res. Commun. 22, 278–284 (1966). doi: .1016/0006-291X(66)90478-5 CrossRefPubMedGoogle Scholar
  3. 3.
    T. Alper, W.A. Cramp, D.A. Haig, M.C. Clarke, Does the agent of Scrapie replicate without nucleic acid? Nature 214, 764–766 (1967). doi: .1038/214764a0 CrossRefPubMedGoogle Scholar
  4. 4.
    Anonymous, National Creutzfeldt-Jakob disease surveillance unit scientific report. Technical report, National Creutzfeldt-Jakob disease surveillance unit, University of Edinburgh, Edinburgh, 2007/08. URL
  5. 5.
    J.A. Beck, M. Poulter, T.A. Campbell, J.B. Uphill, G. Adamson, J.F. Geddes, T. Revesz, M.B. Davis, N.W. Wood, J. Collinge, S.J. Tabrizi, Somatic and germline mosaicism in sporadic early-onset Alzheimer’s disease. Hum. Mol. Genet. 13(12), 1219–1224 (2004). doi: .1093/hmg/ddh134 CrossRefPubMedGoogle Scholar
  6. 6.
    S.C. Bondy, The neurotoxicity of environmental aluminum is still an issue. NeuroToxicology 31(5), 575–581 (2010). doi: .1016/j.neuro.2010.05.009 PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    L. Calderón-Garcidueñas, M. Franco-Lira, A. Mora-Tiscareño, H. Medina-Cortina, R. Torres-Jardón, M. Kavanaugh, Early Alzheimer’s and Parkinson’s disease pathology in urban children: Friend versus foe responses—it is time to face the evidence. BioMed Res. Int. page Article ID 161687 (2013). doi: .1155/2013/161687
  8. 8.
    R.C. Callaghan, J.K. Cunningham, J. Sykes, S.J. Kish, Increased risk of Parkinson’s disease in individuals hospitalized with conditions related to the use of methamphetamine or other amphetamine-type drugs. Drug Alcohol Depend. 120(1–3), 35–40 (2012). doi: .1016/j.drugalcdep.2011.06.013 CrossRefPubMedGoogle Scholar
  9. 9.
    J.M. Charcot, De la sclérose latérale amyotrophique. Prog. Med. 2(325), 341–453 (1874)Google Scholar
  10. 10.
    D.R. Crapper, S.S. Krishnan, S. Quittkat, Aluminium, neurofibrillary degeneration and Alzheimer’s disease. Brain 99(1), 67–80 (1976). doi: .1093/brain/99.1.67 CrossRefPubMedGoogle Scholar
  11. 11.
    H.G. Creutzfeld, Ueber eine eigenartige herdförmige Erkrankung des Zentralnervensystems. Ztschr. ges. Neurol. Psychiat. 57, 1–18 (1924)CrossRefGoogle Scholar
  12. 12.
    B. Da Costa Diasa, K. Jovanovica, D. Gonsalvesa, S.F.T. Weiss, Structural and mechanistic commonalities of amyloid-\(\upbeta\) and the prion protein. Prion 5(3), 126–137 (2011). doi: .4161/pri.5.3.17025 CrossRefGoogle Scholar
  13. 13.
    R. Doll, Review: Alzheimer’s disease and environmental aluminium. Age Ageing 22(2), 138–153 (1993). doi: .1093/ageing/22.2.138 CrossRefPubMedGoogle Scholar
  14. 14.
    Y.S. Eisele, U. Obermüller, G. Heilbronner, F. Baumann, S.A. Kaeser, H. Wolburg, L.C. Walker, M. Staufenbiel, M. Heikenwalder, M. Jucker, Peripherally applied a\(\upbeta\)-containing inoculates induce cerebral \(\upbeta\)-amyloidosis. Science 330, 980–982 (2010). doi: .1126/science.1194516
  15. 15.
    A.C.M. Ferreon, M.M. Moosa, Y. Gambin, A.A. Deniz, Counteracting chemical chaperone effects on the single-molecule \(\upalpha\)-synuclein structural landscape. Proc. Natl. Acad. Sci. USA 109(44), 17826–17831 (2012). doi: .1073/pnas.1201802109 PubMedCentralCrossRefPubMedGoogle Scholar
  16. 16.
    J. Gerstmann, E. Sträussler, I. Scheinker, ber eine eigenartige, hereditär-familiäre Erkrankung des Zentralnervensystems, zugleich ein Beitrag zur Frage des vorzeitigen lokalen Alterns. Z. Neurol. 154, 736–762 (1936). doi: .1007/BF02865827
  17. 17.
    C.J. Gibbs, H.L. Amyx, A. Bacote, C.L. Masters, D.C. Gajdnsek, Oral transmission of Kuru, Creutzfeldt-Jakob disease, and Scrapie to nonhuman primates. J. Infect. Dis. 142(2), 205–208 (1980). doi: .1093/infdis/142.2.205 CrossRefPubMedGoogle Scholar
  18. 18.
    S.M. Goldman, P.J. Quinlan, G.W. Ross, C. Marras, C. Meng, G.S. Bhudhikanok, K. Comyns, M. Korell, A.R. Chade, M. Kasten, B. Priestley, K.L. Chou, H.H. Fernandez, F. Cambi, J.W. Langston, C.M. Tanner, Solvent exposures and Parkinson disease risk in twins. Ann. Neurol. 71(6), 776–784 (2012). doi: .1002/ana.22629 PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    S.M. Gore, W.R. Gilks, J.W. Wilesmith, Bovine spongiform encephalopathy maternal cohort study—exploratory analysis. J. Roy. Stat. Soc. C (Appl. Stat.) 46(3), 305–320 (1997). doi: .1111/1467-9876.00071
  20. 20.
    W. Hadlow, Scrapie and Kuru. Lancet 274(7097), 289–290 (1959). doi: .1016/S0140-6736(59)92081-1 CrossRefGoogle Scholar
  21. 21.
    M. Halliday, H. Radford, G.R. Mallucci, Prions: Generation and spread versus neurotoxicity. J. Biol. Chem. 289(29), 19862–19868 (2014). doi: .1074/jbc.R114.568477 PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    R.D. Hawkins, E.R. Kandel, C.H. Bailey, Molecular mechanisms of memory storage in aplysia. Biol. Bull. 210(3), 174–191 (2006). URL
  23. 23.
    B. Hörnlimann, D. Riesner, H. Kretzschmar, Prionen und Prionkrankheiten (de Gruyter, Berlin, New York, 2001). ISBN 978-3-1101-6361-2Google Scholar
  24. 24.
    G.S. Huntington, On chorea. Med. Surg. Reporter 26, 317–321 (1872). URL
  25. 25.
    W.S. Jackson, Selective vulnerability to neurodegenerative disease: the curious case of prion protein. Dis. Models Mech. 7(1), 21–29 (2014). doi: .1242/dmm.012146 CrossRefGoogle Scholar
  26. 26.
    A. Jakob, Über eigenartige Erkrankungen des Zentralnervensystems mit bemerkenswertem anatomischen Befunde. Z. ges. Neurol. Psychiat. 64(1), 147–228 (1921). doi: .1007/BF02870932 CrossRefGoogle Scholar
  27. 27.
    T. Jonsson, J.K. Atwal, S. Steinberg, J. Snaedal, P.V. Jonsson, S. Bjornsson, H. Stefansson, P. Sulem, D. Gudbjartsson, J. Maloney, K. Hoyte, A. Gustafson, Y. Liu, Y. Lu, T. Bhangale, R.R. Graham, J. Huttenlocher, G. Bjornsdottir, O.A. Andreassen, E.G. Jönsson, A. Palotie, T.W. Behrens, O.T. Magnusson, A. Kong, U. Thorsteinsdottir, R.J. Watts, K. Stefansson, A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature 488(7409), 96–99 (2012). doi: 10.1038/nature11283Google Scholar
  28. 28.
    R. Kayed, Y. Sokolov, B. Edmonds, T.M. McIntire, S.C. Milton, J.E. Hall, C.G. Glabe, Permeabilization of lipid bilayers is a common conformation-dependent activity of soluble amyloid oligomers in protein misfolding diseases. J. Biol. Chem. 279(45), 46363–46366 (2004). doi: .1074/jbc.C400260200 CrossRefPubMedGoogle Scholar
  29. 29.
    B. Keshet, J.J. Gray, T.A. Good, Structurally distinct toxicity inhibitors bind at common loci on \(\upbeta\)-amyloid fibril. Protein Sci. 19, 2291–2304 (2010). doi: .1002/pro.509 PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    J.A. Mastrianni, R. Nixon, R. Layzer, G.C. Telling, D. Han, S.J. DeArmond, S.B. Prusiner, Prion protein conformation in a patient with sporadic fatal insomnia. New Engl. J. Med. 340(21), 1630–1638 (1999). doi: .1056/NEJM199905273402104 CrossRefPubMedGoogle Scholar
  31. 31.
    D.T. Max, The Family That Couldn’t Sleep—Unravelling a Venetian Medical Mystery (Portobello, London, 2007). ISBN 978-1-84627-089-5Google Scholar
  32. 32.
    K.L. Murray, Vertical transmission of variant CJD. J. Neurol. Neurosurg. Psychiat. 76(9), 1318 (2005). URL
  33. 33.
    G. Natalea, M. Ferruccia, G. Lazzeria, A. Paparellia, F. Fornai, Transmission of prions within the gut and towards the central nervous system. Prion 5(3), 142–149 (2011). doi: .4161/pri.5.3.16328 CrossRefGoogle Scholar
  34. 34.
    J.M. Nussbaum, M.E. Seward, G.S. Bloom, Alzheimer disease: A tale of two prions. Prion 7(1), 14–19 (2013). doi: .4161/pri.22118 PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    F. Pan-Montojo, M. Schwarz, C. Winkler, M. Arnhold, G.A. O’Sullivan, A. Pal, J. Said, G. Marsico, J.-M. Verbavatz, M. Rodrigo-Angulo, G. Gille, R.H.W. Funk, H. Reichmann, Environmental toxins trigger PD-like progression via increased alpha-synuclein release from enteric neurons in mice. Sci. Rep. 2, Article number 898 (2012). doi: .1038/srep00898
  36. 36.
  37. 37.
    S.B. Prusiner, Prions. Proc. Natl. Acad. Sci. USA 95, 13363–13383 (1998). doi: .1073/pnas.95.23.13363 CrossRefPubMedGoogle Scholar
  38. 38.
    S.B. Prusiner, Biology and genetics of prions causing neurodegeneration. Annu. Rev. Genet. 47, 601–623 (2013). doi: .1146/annurev-genet-110711-155524 PubMedCentralCrossRefPubMedGoogle Scholar
  39. 39.
    J.R. Requena, H Wille, The structure of the infectious prion protein: Experimental data and molecular models. Prion 8(1), 60–66 (2014). doi: .4161/pri.28368 PubMedGoogle Scholar
  40. 40.
    A. Samsel, S. Seneff, Glyphosate’s suppression of cytochrome P450 enzymes and amino acid biosynthesis by the gut microbiome: Pathways to modern diseases. Entropy 15(4),1416–1463 (2013). doi: .3390/e15041416 CrossRefGoogle Scholar
  41. 41.
    S. Semar, M. Klotz, M. Letiembre, C. Van Ginneken, A. Braun, V. Jost, M. Bischof, W.J. Lammers, Y. Liu, K. Fassbender, T. Wyss-Coray, F. Kirchhoff, K.-H. Schäfer, Changes of the enteric nervous system in amyloid-β protein precursor transgenic mice correlate with disease progression. J. Alzheimer’s Dis. 36(1), 7–20 (2013). doi: .3233/jad-120511 Google Scholar
  42. 42.
    M. Thiruchelvam, B.J. Brockel, E.K. Richfield, R.B. Baggs, D.A. Cory-Slechta, Potentiated and preferential effects of combined paraquat and maneb on nigrostriatal dopamine systems: environmental risk factors for Parkinson’s disease? Brain Res. 873, 225–234 (2000). doi: .1016/S0006-8993(00)02496-3 CrossRefPubMedGoogle Scholar
  43. 43.
    R. Virchow, Ueber eine im Gehirn und Rückenmark des Menschen aufgefundene Substanz mit der chemischen Reaction der Cellulose. Virchows Arch. path. Anat. Physiol. Klin. Med. 6(1), 135–138 (1854). doi: .1007/BF01930815 CrossRefGoogle Scholar
  44. 44.
    F. Wang, X. Wang, C.-G. Yuan, J. Ma, Generating a prion with bacterially expressed recombinant prion protein. Science 327, 1132–1135 (2010). doi: .1126/science.1183748 PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Engelbert Buxbaum
    • 1
  1. 1.KevelaerGermany

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