Prion-like mechanisms in neurodegenerative diseases

Abstract

Many non-infectious neurodegenerative diseases are associated with the accumulation of fibrillar proteins. These diseases all exhibit features that are reminiscent of those of prionopathies, including phenotypic diversity and the propagation of pathology. Furthermore, emerging studies of amyloid-β, α-synuclein and tau — proteins implicated in common neurodegenerative diseases — suggest that they share key biophysical and biochemical characteristics with prions. Propagation of protein misfolding in these diseases may therefore occur through mechanisms similar to those that underlie prion pathogenesis. If this hypothesis is verified in vivo, it will suggest new therapeutic strategies to block propagation of protein misfolding throughout the brain.

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Figure 1: Potential mechanisms for trans-cellular propagation of protein misfolding.
Figure 2: New therapeutic approaches.

References

  1. 1

    Prusiner, S. B. Novel proteinaceous infectious particles cause scrapie. Science 216, 136–144 (1982).

    CAS  Article  Google Scholar 

  2. 2

    Caughey, B., Race, R. E. & Chesebro, B. Detection of prion protein mRNA in normal and scrapie-infected tissues and cell lines. J. Gen. Virol. 69, 711–716 (1988).

    CAS  Article  PubMed  Google Scholar 

  3. 3

    Pan, K. M. et al. Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins. Proc. Natl Acad. Sci. USA 90, 10962–10966 (1993).

    CAS  Article  PubMed  Google Scholar 

  4. 4

    Prusiner, S. B. Prions. Proc. Natl Acad. Sci. USA 95, 13363–13383 (1998).

    CAS  Article  Google Scholar 

  5. 5

    Williamson, J., Goldman, J. & Marder, K. S. Genetic aspects of Alzheimer disease. Neurologist 15, 80–86 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  6. 6

    Armstrong, R. A., Nochlin, D. & Bird, T. D. Neuropathological heterogeneity in Alzheimer's disease: a study of 80 cases using principal components analysis. Neuropathology 20, 31–37 (2000).

    CAS  Article  PubMed  Google Scholar 

  7. 7

    Chui, H. C., Teng, E. L., Henderson, V. W. & Moy, A. C. Clinical subtypes of dementia of the Alzheimer type. Neurology 35, 1544–1550 (1985).

    CAS  Article  PubMed  Google Scholar 

  8. 8

    Askanas, V. & Engel, W. K. Inclusion-body myositis: a myodegenerative conformational disorder associated with Aβ, protein misfolding, and proteasome inhibition. Neurology 66, S39–S48 (2006).

    CAS  Article  PubMed  Google Scholar 

  9. 9

    Glenner, G. G. & Wong, C. W. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun. 120, 885–890 (1984).

    CAS  Article  Google Scholar 

  10. 10

    Goedert, M. et al. From genetics to pathology: tau and alpha-synuclein assemblies in neurodegenerative diseases. Philos. Trans. R. Soc. Lond. B Biol. Sci. 356, 213–227 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11

    Polymeropoulos, M. H. et al. Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science 276, 2045–2047 (1997).

    CAS  Article  PubMed  Google Scholar 

  12. 12

    Zarranz, J. J. et al. The new mutation, E46K, of α-synuclein causes Parkinson and Lewy body dementia. Ann. Neurol. 55, 164–173 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13

    Ibanez, P. et al. Causal relation between α-synuclein gene duplication and familial Parkinson's disease. Lancet 364, 1169–1171 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14

    Singleton, A. B. et al. α-Synuclein locus triplication causes Parkinson's disease. Science 302, 841 (2003).

    CAS  Article  PubMed  Google Scholar 

  15. 15

    Chartier-Harlin, M. C. et al. α-Synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 364, 1167–1169 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16

    Ironside, J. W., Ritchie, D. L. & Head, M. W. Phenotypic variability in human prion diseases. Neuropathol. Appl. Neurobiol. 31, 565–579 (2005).

    CAS  Article  PubMed  Google Scholar 

  17. 17

    Wadsworth, J. D. & Collinge, J. Update on human prion disease. Biochim. Biophys. Acta 1772, 598–609 (2007).

    CAS  Article  PubMed  Google Scholar 

  18. 18

    Hsiao, K. et al. Linkage of a prion protein missense variant to Gerstmann-Straussler syndrome. Nature 338, 342–345 (1989).

    CAS  Article  PubMed  Google Scholar 

  19. 19

    Gajdusek, D. C. Unconventional viruses and the origin and disappearance of kuru. Science 197, 943–960 (1977).

    CAS  Article  PubMed  Google Scholar 

  20. 20

    Prusiner, S. B. Prion diseases and the BSE crisis. Science 278, 245–251 (1997).

    CAS  Article  PubMed  Google Scholar 

  21. 21

    Bessen, R. A. et al. Non-genetic propagation of strain-specific properties of scrapie prion protein. Nature 375, 698–700 (1995).

    CAS  Article  PubMed  Google Scholar 

  22. 22

    Telling, G. C. et al. Evidence for the conformation of the pathologic isoform of the prion protein enciphering and propagating prion diversity. Science 274, 2079–2082 (1996).

    CAS  Article  PubMed  Google Scholar 

  23. 23

    Safar, J. et al. Eight prion strains have PrPSc molecules with different conformations. Nature Med. 4, 1157–1165 (1998).

    CAS  Article  PubMed  Google Scholar 

  24. 24

    Legname, G. et al. Continuum of prion protein structures enciphers a multitude of prion isolate-specified phenotypes. Proc. Natl Acad. Sci. USA 103, 19105–19110 (2006).

    CAS  Article  Google Scholar 

  25. 25

    Tanaka, M., Collins, S. R., Toyama, B. H. & Weissman, J. S. The physical basis of how prion conformations determine strain phenotypes. Nature 442, 585–589 (2006).

    CAS  Article  Google Scholar 

  26. 26

    Toyama, B. H., Kelly, M. J., Gross, J. D. & Weissman, J. S. The structural basis of yeast prion strain variants. Nature 449, 233–237 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27

    Frost, B., Ollesch, J., Wille, H. & Diamond, M. I. Conformational diversity of wild-type Tau fibrils specified by templated conformation change. J. Biol. Chem. 284, 3546–3551 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28

    Petkova, A. T. et al. Self-propagating, molecular-level polymorphism in Alzheimer's β-amyloid fibrils. Science 307, 262–265 (2005).

    CAS  Article  Google Scholar 

  29. 29

    Yonetani, M. et al. Conversion of wild-type α-synuclein into mutant-type fibrils and its propagation in the presence of A30P mutant. J. Biol. Chem. 284, 7940–7950 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30

    von Bergen, M. et al. Assembly of tau protein into Alzheimer paired helical filaments depends on a local sequence motif (306VQIVYK311) forming β structure. Proc. Natl Acad. Sci. USA 97, 5129–5134 (2000).

    CAS  Article  PubMed  Google Scholar 

  31. 31

    Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. (Berl.) 82, 239–259 (1991).

    CAS  Article  Google Scholar 

  32. 32

    Seeley, W. W., Crawford, R. K., Zhou, J., Miller, B. L. & Greicius, M. D. Neurodegenerative diseases target large-scale human brain networks. Neuron 62, 42–52 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33

    Hobson, P. & Meara, J. The detection of dementia and cognitive impairment in a community population of elderly people with Parkinson's disease by use of the CAMCOG neuropsychological test. Age Ageing 28, 39–43 (1999).

    CAS  Article  PubMed  Google Scholar 

  34. 34

    Cudkowicz, M., Qureshi, M. & Shefner, J. Measures and markers in amyotrophic lateral sclerosis. NeuroRx 1, 273–283 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  35. 35

    Brown, P., Preece, M. A. & Will, R. G. “Friendly fire” in medicine: hormones, homografts, and Creutzfeldt-Jakob disease. Lancet 340, 24–27 (1992).

    CAS  Article  PubMed  Google Scholar 

  36. 36

    Beekes, M., McBride, P. A. & Baldauf, E. Cerebral targeting indicates vagal spread of infection in hamsters fed with scrapie. J. Gen. Virol. 79, 601–607 (1998).

    CAS  Article  PubMed  Google Scholar 

  37. 37

    Fraser, H. Neuronal spread of scrapie agent and targeting of lesions within the retino-tectal pathway. Nature 295, 149–150 (1982).

    CAS  Article  PubMed  Google Scholar 

  38. 38

    Brandner, S. et al. Normal host prion protein (PrPC) is required for scrapie spread within the central nervous system. Proc. Natl Acad. Sci. USA 93, 13148–13151 (1996).

    CAS  Article  PubMed  Google Scholar 

  39. 39

    Magalhaes, A. C. et al. Uptake and neuritic transport of scrapie prion protein coincident with infection of neuronal cells. J. Neurosci. 25, 5207–5216 (2005).

    CAS  Article  PubMed  Google Scholar 

  40. 40

    Fevrier, B. et al. Cells release prions in association with exosomes. Proc. Natl Acad. Sci. USA 101, 9683–9688 (2004).

    CAS  Article  Google Scholar 

  41. 41

    Gousset, K. et al. Prions hijack tunnelling nanotubes for intercellular spread. Nature Cell Biol. 11, 328–336 (2009).

    CAS  Article  Google Scholar 

  42. 42

    Gerdes, H. H. & Carvalho, R. N. Intercellular transfer mediated by tunneling nanotubes. Curr. Opin. Cell Biol. 20, 470–475 (2008).

    CAS  Article  PubMed  Google Scholar 

  43. 43

    Li, J. Y. et al. Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nature Med. 14, 501–503 (2008).

    CAS  Article  Google Scholar 

  44. 44

    Kordower, J. H., Chu, Y., Hauser, R. A., Olanow, C. W. & Freeman, T. B. Transplanted dopaminergic neurons develop PD pathologic changes: a second case report. Mov. Disord. 23, 2303–2306 (2008).

    Article  Google Scholar 

  45. 45

    Kordower, J. H., Chu, Y., Hauser, R. A., Freeman, T. B. & Olanow, C. W. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease. Nature Med. 14, 504–506 (2008).

    CAS  Article  PubMed  Google Scholar 

  46. 46

    Desplats, P. et al. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein. Proc. Natl Acad. Sci. USA 106, 13010–13015 (2009).

    CAS  Article  Google Scholar 

  47. 47

    Yang, W., Dunlap, J. R., Andrews, R. B. & Wetzel, R. Aggregated polyglutamine peptides delivered to nuclei are toxic to mammalian cells. Hum. Mol. Genet. 11, 2905–2917 (2002).

    CAS  Article  PubMed  Google Scholar 

  48. 48

    Lee, H. J. et al. Assembly-dependent endocytosis and clearance of extracellular α-synuclein. Int. J. Biochem. Cell Biol. 40, 1835–1849 (2008).

    CAS  Article  Google Scholar 

  49. 49

    Frost, B., Jacks, R. L. & Diamond, M. I. Propagation of tau misfolding from the outside to the inside of a cell. J. Biol. Chem. 284, 12845–12852 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50

    Ren, P. H. et al. Cytoplasmic penetration and persistent infection of mammalian cells by polyglutamine aggregates. Nature Cell Biol. 11, 219–225 (2009).

    CAS  Article  Google Scholar 

  51. 51

    Krammer, C. et al. The yeast Sup35NM domain propagates as a prion in mammalian cells. Proc. Natl Acad. Sci. USA 106, 462–467 (2009).

    CAS  Article  PubMed  Google Scholar 

  52. 52

    Meyer-Luehmann, M. et al. Exogenous induction of cerebral β-amyloidogenesis is governed by agent and host. Science 313, 1781–1784 (2006).

    CAS  Article  PubMed  Google Scholar 

  53. 53

    Clavaguera, F. et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nature Cell Biol. 11, 909–913 (2009).

    CAS  Article  PubMed  Google Scholar 

  54. 54

    Werdelin, O. & Ranlov, P. Amyloidosis in mice produced by transplantation of spleen cells from casein-treated mice. Acta Pathol. Microbiol. Scand. 68, 1–18 (1966).

    CAS  Article  PubMed  Google Scholar 

  55. 55

    Westermark, G. T. & Westermark, P. Serum amyloid A and protein AA: molecular mechanisms of a transmissible amyloidosis. FEBS Lett. 583, 2685–2690 (2009).

    CAS  Article  PubMed  Google Scholar 

  56. 56

    Lundmark, K. et al. Transmissibility of systemic amyloidosis by a prion-like mechanism. Proc. Natl Acad. Sci. USA 99, 6979–6984 (2002).

    CAS  Article  PubMed  Google Scholar 

  57. 57

    Mendez, O. E., Shang, J., Jungreis, C. A. & Kaufer, D. I. Diffusion-weighted MRI in Creutzfeldt-Jakob disease: a better diagnostic marker than CSF protein 14-3-3? J. Neuroimaging 13, 147–151 (2003).

    Article  PubMed  Google Scholar 

  58. 58

    Asuni, A. A., Boutajangout, A., Quartermain, D. & Sigurdsson, E. M. Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. J. Neurosci. 27, 9115–9129 (2007).

    CAS  Article  Google Scholar 

  59. 59

    Masliah, E. et al. Effects of α-synuclein immunization in a mouse model of Parkinson's disease. Neuron 46, 857–868 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60

    Nekooki-Machida, Y. et al. Distinct conformations of in vitro and in vivo amyloids of huntingtin-exon1 show different cytotoxicity. Proc. Natl Acad. Sci. USA 106, 9679–9684 (2009).

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

B.F. gratefully acknowledges support from a training grant from the National Institute of Neurological Disorders and Stroke (NINDS). M.I.D. gratefully acknowledges support from the Sandler Family Supporting Foundation, the Muscular Dystrophy Association and NINDS.

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Correspondence to Marc I. Diamond.

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Alzheimer's disease

dementia with Lewy bodies

frontotemporal dementia

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Parkinson's disease

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Frost, B., Diamond, M. Prion-like mechanisms in neurodegenerative diseases. Nat Rev Neurosci 11, 155–159 (2010). https://doi.org/10.1038/nrn2786

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