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Prion-like transmission of protein aggregates in neurodegenerative diseases

Nature Reviews Molecular Cell Biology volume 11, pages 301–307 (2010)Cite this article

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Abstract

Neurodegenerative diseases are commonly associated with the accumulation of intracellular or extracellular protein aggregates. Recent studies suggest that these aggregates are capable of crossing cellular membranes and can directly contribute to the propagation of neurodegenerative disease pathogenesis. We propose that, once initiated, neuropathological changes might spread in a 'prion-like' manner and that disease progression is associated with the intercellular transfer of pathogenic proteins. The transfer of naked infectious particles between cells could therefore be a target for new disease-modifying therapies.

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Figure 1: Basic mechanisms of protein aggregation.
Figure 2: Potential pathways of uptake and release of protein aggregates by cells.
Figure 3: Principles for progression of neuropathological changes.

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References

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Uversky, V. N. Neuropathology, biochemistry, and biophysics of α-synuclein aggregation. J. Neurochem. 103, 17–37 (2007).

    CAS  PubMed  Google Scholar 

  4. Braak, H., Ghebremedhin, E., Rub, U., Bratzke, H. & Del Tredici, K. Stages in the development of Parkinson's disease-related pathology. Cell Tissue Res. 318, 121–134 (2004).

    Article  Google Scholar 

  5. Braak, H. et al. Stanley Fahn Lecture 2005: The staging procedure for the inclusion body pathology associated with sporadic Parkinson's disease reconsidered. Mov. Disord. 21, 2042–2051 (2006).

    Article  Google Scholar 

  6. Hawkes, C. H., Del Tredici, K. & Braak, H. Parkinson's disease: a dual-hit hypothesis. Neuropathol. Appl. Neurobiol. 33, 599–614 (2007).

    Article  CAS  Google Scholar 

  7. Jang, H. et al. Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration. Proc. Natl Acad. Sci. USA 106, 14063–14068 (2009).

    Article  CAS  Google Scholar 

  8. Jang, H., Boltz, D. A., Webster, R. G. & Smeyne, R. J. Viral parkinsonism. Biochim. Biophys. Acta 1792, 714–721 (2009).

    Article  CAS  Google Scholar 

  9. Burke, R. E., Dauer, W. T. & Vonsattel, J. P. A critical evaluation of the Braak staging scheme for Parkinson's disease. Ann. Neurol. 64, 485–491 (2008).

    Article  Google Scholar 

  10. Jellinger, K. A. Formation and development of Lewy pathology: a critical update. J. Neurol. 256 270–279 (2009).

    Article  Google Scholar 

  11. Nelson, P. T., Braak, H. & Markesbery, W. R. Neuropathology and cognitive impairment in Alzheimer disease: a complex but coherent relationship. J. Neuropathol. Exp. Neurol. 68, 1–14 (2009).

    Article  CAS  Google Scholar 

  12. Duyckaerts, C., Delatour, B. & Potier, M. C. Classification and basic pathology of Alzheimer disease. Acta Neuropathol. 118, 5–36 (2009).

    Article  CAS  Google Scholar 

  13. Goedert, M., Klug, A. & Crowther, R. A. Tau protein, the paired helical filament and Alzheimer's disease. J. Alzheimers Dis. 9, 195–207 (2006).

    Article  CAS  Google Scholar 

  14. Selkoe, D. J. Alzheimer's disease: genes, proteins, and therapy. Physiol. Rev. 81, 741–766 (2001).

    Article  CAS  Google Scholar 

  15. Pearson, R. C., Esiri, M. M., Hiorns, R. W., Wilcock, G. K. & Powell, T. P. Anatomical correlates of the distribution of the pathological changes in the neocortex in Alzheimer disease. Proc. Natl Acad. Sci. USA 82, 4531–4534 (1985).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  17. Delacourte, A. et al. Tau aggregation in the hippocampal formation: an ageing or a pathological process? Exp. Gerontol. 37, 1291–1296 (2002).

    Article  CAS  Google Scholar 

  18. Lace, G. et al. Hippocampal tau pathology is related to neuroanatomical connections: an ageing population-based study. Brain 132, 1324–1334 (2009).

    Article  CAS  Google Scholar 

  19. Arriagada, P. V., Growdon, J. H., Hedley-Whyte, E. T. & Hyman, B. T. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology 42, 631–639 (1992).

    Article  CAS  Google Scholar 

  20. Cattaneo, E., Zuccato, C. & Tartari, M. Normal huntingtin function: an alternative approach to Huntington's disease. Nature Rev. Neurosci. 6, 919–930 (2005).

    Article  CAS  Google Scholar 

  21. Davies, S. W. et al. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90, 537–548 (1997).

    Article  CAS  Google Scholar 

  22. DiFiglia, M. et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277, 1990–1993 (1997).

    Article  CAS  Google Scholar 

  23. Scherzinger, E. et al. Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo. Cell 90, 549–558 (1997).

    Article  CAS  Google Scholar 

  24. Duyao, M. et al. Trinucleotide repeat length instability and age of onset in Huntington's disease. Nature Genet. 4, 387–392 (1993).

    Article  CAS  Google Scholar 

  25. Vonsattel, J. P. & DiFiglia, M. Huntington disease. J. Neuropathol. Exp. Neurol. 57, 369–384 (1998).

    Article  CAS  Google Scholar 

  26. Deng, Y. P. et al. Differential loss of striatal projection systems in Huntington's disease: a quantitative immunohistochemical study. J. Chem. Neuroanat. 27, 143–164 (2004).

    Article  CAS  Google Scholar 

  27. Kipps, C. M. et al. Progression of structural neuropathology in preclinical Huntington's disease: a tensor based morphometry study. J. Neurol. Neurosurg. Psychiatr. 76, 650–655 (2005).

    Article  CAS  Google Scholar 

  28. Rosas, H. D. et al. Cerebral cortex and the clinical expression of Huntington's disease: complexity and heterogeneity. Brain 131, 1057–1068 (2008).

    Article  Google Scholar 

  29. Brundin, P., Li, J. Y., Holton, J. L., Lindvall, O. & Revesz, T. Research in motion: the enigma of Parkinson's disease pathology spread. Nature Rev. Neursci. 9, 741–745 (2008).

    Article  CAS  Google Scholar 

  30. 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).

    Article  CAS  Google Scholar 

  31. 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 

  32. 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).

    Article  CAS  Google Scholar 

  33. Li, J. Y. et al. Characterization of Lewy body pathology in 12- and 16-year old intrastriatal mesencephalic grafts surviving in a patient with Parkinson's disease. Mov. Disord. 2 Mar 2010 (doi:10.1002/mds.23012).

  34. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  36. Danzer, K. M., Krebs, S. K., Wolff, M., Birk, G. & Hengerer, B. Seeding induced by α-synuclein oligomers provides evidence for spreading of α-synuclein pathology. J. Neurochem. 111, 192–203 (2009).

    Article  CAS  Google Scholar 

  37. Danzer, K. M. et al. Different species of α-synuclein oligomers induce calcium influx and seeding. J. Neurosci. 27, 9220–9232 (2007).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  40. Clavaguera, F. et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nature Cell Biol. 11, 907–913 (2009).

    Article  Google Scholar 

  41. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  43. Rujano, M. A. et al. Polarised asymmetric inheritance of accumulated protein damage in higher eukaryotes. PLoS Biol. 4, e417 (2006).

    Article  Google Scholar 

  44. Cicchetti, F. et al. Neural transplants in patients with Huntington's disease undergo disease-like neuronal degeneration. Proc. Natl Acad. Sci. USA 106, 12483–12488 (2009).

    Article  CAS  Google Scholar 

  45. Vogiatzi, T., Xilouri, M., Vekrellis, K. & Stefanis, L. Wild type α-synuclein is degraded by chaperone-mediated autophagy and macroautophagy in neuronal cells. J. Biol. Chem. 283, 23542–23556 (2008).

    Article  CAS  Google Scholar 

  46. Jaiswal, J. K., Fix, M., Takano, T., Nedergaard, M. & Simon, S. M. Resolving vesicle fusion from lysis to monitor calcium-triggered lysosomal exocytosis in astrocytes. Proc. Natl Acad. Sci. USA 104, 14151–14156 (2007).

    Article  CAS  Google Scholar 

  47. Lee, H. J., Patel, S. & Lee, S. J. Intravesicular localization and exocytosis of α-synuclein and its aggregates. J. Neurosci. 25, 6016–6024 (2005).

    Article  CAS  Google Scholar 

  48. Morten, I. J., Gosal, W. S., Radford, S. E. & Hewitt, E. W. Investigation into the role of macrophages in the formation and degradation of β2-microglobulin amyloid fibrils. J. Biol. Chem. 282, 29691–29700 (2007).

    Article  CAS  Google Scholar 

  49. Bucciantini, M. et al. Prefibrillar amyloid protein aggregates share common features of cytotoxicity. J. Biol. Chem. 279, 31374–31382 (2004).

    Article  CAS  Google Scholar 

  50. van Rooijen, B. D., Claessens, M. M. & Subramaniam, V. Lipid bilayer disruption by oligomeric α-synuclein depends on bilayer charge and accessibility of the hydrophobic core. Biochim. Biophys. Acta 1788, 1271–1278 (2009).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  52. Brown, R. A brief account of microscopical observations made in the month of June, July and August, 1827, on the particles contained in the pollen of plants; and on the general existence of active molecules in organic and inorganic bodies. Phil. Mag. 4, 161–173 (1828).

    Article  Google Scholar 

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Acknowledgements

All three investigators are supported by a joint Human Frontier Science Program grant on the topic relevant to this article. In addition, P.B. holds related grants from the MJ Fox Foundation for Parkinson's Research, Swedish Brain Foundation, Swedish Parkinson Foundation, Söderberg Foundation and the Swedish Research Council. R.R.K. is supported by the Huntington's disease Society of America Coalition for the Cure, the CHDI Foundation and the National Institute of Neurological Disease and Stroke. R.M. is supported by the Agence Nationale de la Recherche and the Centre National de la Recherche Scientifique. R.M. and P.B. are part of the ERA-net Neuron program MIPROTRAN.

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Authors and Affiliations

  1. Patrik Brundin is at the Neuronal Survival Unit, Wallenberg Neuroscience Center, Lund University, BMC A10, 221 84 Lund, Sweden. patrik.brundin@med.lu.se,

    Patrik Brundin

  2. Ronald Melki is at the Laboratoire d'Enzymologie et Biochimie Structurales, Centre National de la Recherche Scientifique, 91198 Gif–sur–Yvette, France. melki@lebs.cnrs-gif.fr,

    Ronald Melki

  3. Ron Kopito is at the Department of Biology, Stanford University, Stanford, California 94305–5020, USA. kopito@stanford.edu,

    Ron Kopito

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Brundin, P., Melki, R. & Kopito, R. Prion-like transmission of protein aggregates in neurodegenerative diseases. Nat Rev Mol Cell Biol 11, 301–307 (2010). https://doi.org/10.1038/nrm2873

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