Abstract
Prion science has been on a rollercoaster for two decades. In the mid 1990s, the specter of mad cow disease (bovine spongiform encephalopathy, BSE) provoked an unprecedented public scare that was first precipitated by the realization that this animal prion disease could be transmitted to humans and then rekindled by the evidence that BSE-infected humans could pass on the infection through blood transfusions. Along with the gradual disappearance of BSE, the interest in prions has waned with the general public, funding agencies and prospective PhD students. In the past few years, however, a bewildering variety of diseases have been found to share features with prion infections, including cell-to-cell transmission. Here we review these developments and summarize those open questions that we currently deem most interesting in prion biology: how do prions damage their hosts, and how do hosts attempt to neutralize invading prions?
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Büeler, H. et al. Mice devoid of PrP are resistant to scrapie. Cell 73, 1339–1347 (1993).
Prusiner, S.B. Novel proteinaceous infectious particles cause scrapie. Science 216, 136–144 (1982).
Knowles, T.P. et al. An analytical solution to the kinetics of breakable filament assembly. Science 326, 1533–1537 (2009).
Saborio, G.P., Permanne, B. & Soto, C. Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding. Nature 411, 810–813 (2001).
Castilla, J., Saa, P., Hetz, C. & Soto, C. In vitro generation of infectious scrapie prions. Cell 121, 195–206 (2005).
Deleault, N.R., Harris, B.T., Rees, J.R. & Supattapone, S. Formation of native prions from minimal components in vitro. Proc. Natl. Acad. Sci. USA 104, 9741–9746 (2007).
Wang, F., Wang, X., Yuan, C.G. & Ma, J. Generating a prion with bacterially expressed recombinant prion protein. Science 327, 1132–1135 (2010).
Lesné, S. et al. A specific amyloid-beta protein assembly in the brain impairs memory. Nature 440, 352–357 (2006).
Shankar, G.M. et al. Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat. Med. 14, 837–842 (2008).
Laurén, J., Gimbel, D.A., Nygaard, H.B., Gilbert, J.W. & Strittmatter, S.M. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature 457, 1128–1132 (2009).
Riek, R., Hornemann, S., Wider, G., Glockshuber, R. & Wüthrich, K. NMR characterization of the full-length recombinant murine prion protein, mPrP(23–231). FEBS Lett 413, 282–288 (1997).
Balducci, C. et al. Synthetic amyloid-beta oligomers impair long-term memory independently of cellular prion protein. Proc. Natl. Acad. Sci. USA 107, 2295–2300 (2010).
Cissé, M. et al. Ablation of cellular prion protein does not ameliorate abnormal neural network activity or cognitive dysfunction in the J20 line of human amyloid precursor protein transgenic mice. J. Neurosci. 31, 10427–10431 (2011).
Calella, A.M. et al. Prion protein and Abeta-related synaptic toxicity impairment. EMBO Mol. Med. 2, 306–314 (2010).
Gimbel, D.A. et al. Memory impairment in transgenic Alzheimer mice requires cellular prion protein. J. Neurosci. 30, 6367–6374 (2010).
Freir, D.B. et al. Interaction between prion protein and toxic amyloid β assemblies can be therapeutically targeted at multiple sites. Nat. Commun. 2, 336 (2011).
Barry, A.E. et al. Alzheimer's disease brain-derived amyloid-β-mediated inhibition of LTP in vivo is prevented by immunotargeting cellular prion protein. J. Neurosci. 31, 7259–7263 (2011).
Benilova, I., Karran, E. & De Strooper, B. The toxic Abeta oligomer and Alzheimer's disease: an emperor in need of clothes. Nat. Neurosci. 15, 349–357 (2012).
Brandner, S. et al. Normal host prion protein necessary for scrapie-induced neurotoxicity. Nature 379, 339–343 (1996).
Mallucci, G. et al. Depleting neuronal PrP in prion infection prevents disease and reverses spongiosis. Science 302, 871–874 (2003).
Chesebro, B. et al. Anchorless prion protein results in infectious amyloid disease without clinical scrapie. Science 308, 1435–1439 (2005).
Solforosi, L. et al. Cross-linking cellular prion protein triggers neuronal apoptosis in vivo. Science 303, 1514–1516 (2004).
Shmerling, D. et al. Expression of amino-terminally truncated PrP in the mouse leading to ataxia and specific cerebellar lesions. Cell 93, 203–214 (1998).
Sandberg, M.K., Al-Doujaily, H., Sharps, B., Clarke, A.R. & Collinge, J. Prion propagation and toxicity in vivo occur in two distinct mechanistic phases. Nature 470, 540–542 (2011).
Büeler, H. et al. High prion and PrPSc levels but delayed onset of disease in scrapie-inoculated mice heterozygous for a disrupted PrP gene. Mol. Med. 1, 19–30 (1994).
Stöhr, J. et al. Spontaneous generation of anchorless prions in transgenic mice. Proc. Natl. Acad. Sci. USA 108, 21223–21228 (2011).
Aguzzi, A. & Calella, A.M. Prions: protein aggregation and infectious diseases. Physiol. Rev. 89, 1105–1152 (2009).
Khosravani, H. et al. Prion protein attenuates excitotoxicity by inhibiting NMDA receptors. J. Cell Biol. 181, 551–565 (2008).
You, H. et al. Abeta neurotoxicity depends on interactions between copper ions, prion protein and N-methyl-D-aspartate receptors. Proc. Natl. Acad. Sci. USA 109, 1737–1742 (2012).
Ma, J. & Lindquist, S. Wild-type PrP and a mutant associated with prion disease are subject to retrograde transport and proteasome degradation. Proc. Natl. Acad. Sci. USA 98, 14955–14960 (2001).
Hegde, R.S. et al. A transmembrane form of the prion protein in neurodegenerative disease. Science 279, 827–834 (1998).
Chakrabarti, O. & Hegde, R.S. Functional depletion of mahogunin by cytosolically exposed prion protein contributes to neurodegeneration. Cell 137, 1136–1147 (2009).
Aguzzi, A. & Steele, A.D. Prion topology and toxicity. Cell 137, 994–996 (2009).
Behrens, A. & Aguzzi, A. Small is not beautiful: antagonizing functions for the prion protein PrP(C) and its homologue Dpl. Trends Neurosci. 25, 150–154 (2002).
Solomon, I.H., Huettner, J.E. & Harris, D.A. Neurotoxic mutants of the prion protein induce spontaneous ionic currents in cultured cells. J. Biol. Chem. 285, 26719–26726 (2010).
Solomon, I.H. et al. An N-terminal polybasic domain and cell surface localization are required for mutant prion protein toxicity. J. Biol. Chem. 286, 14724–14736 (2011).
Solomon, I.H., Biasini, E. & Harris, D.A. Ion channels induced by the prion protein: mediators of neurotoxicity. Prion 6, 40–45 (2012).
Bellinger-Kawahara, C., Cleaver, J.E., Diener, T.O. & Prusiner, S.B. Purified scrapie prions resist inactivation by UV irradiation. J. Virol. 61, 159–166 (1987).
Brown, P. & Gajdusek, D.C. Survival of scrapie virus after 3 years' interment. Lancet 337, 269–270 (1991).
Peretz, D. et al. Antibodies inhibit prion propagation and clear cell cultures of prion infectivity. Nature 412, 739–743 (2001).
Safar, J.G. et al. Prion clearance in bigenic mice. J. Gen. Virol. 86, 2913–2923 (2005).
Chernoff, Y.O., Lindquist, S.L., Ono, B., Inge Vechtomov, S.G. & Liebman, S.W. Role of the chaperone protein Hsp104 in propagation of the yeast prion-like factor. Science 268, 880–884 (1995).
Luhr, K.M. et al. Scrapie protein degradation by cysteine proteases in CD11c(+) dendritic cells and GT1-1 neuronal cells. J. Virol. 78, 4776–4782 (2004).
Beringue, V. et al. Role of spleen macrophages in the clearance of scrapie agent early in pathogenesis. J. Pathol. 190, 495–502 (2000).
Falsig, J. et al. A versatile prion replication assay in organotypic brain slices. Nat. Neurosci. 11, 109–117 (2008).
Flores-Langarica, A., Sebti, Y., Mitchell, D.A., Sim, R.B. & MacPherson, G.G. Scrapie pathogenesis: the role of complement C1q in scrapie agent uptake by conventional dendritic cells. J. Immunol. 182, 1305–1313 (2009).
Baker, C.A., Martin, D. & Manuelidis, L. Microglia from Creutzfeldt-Jakob disease–infected brains are infectious and show specific mRNA activation profiles. J. Virol. 76, 10905–10913 (2002).
Kranich, J. et al. Engulfment of cerebral apoptotic bodies controls the course of prion disease in a mouse strain–dependent manner. J. Exp. Med. 207, 2271–2281 (2010).
Ghaemmaghami, S. et al. Cell division modulates prion accumulation in cultured cells. Proc. Natl. Acad. Sci. USA 104, 17971–17976 (2007).
Mahal, S.P. et al. Prion strain discrimination in cell culture: the cell panel assay. Proc. Natl. Acad. Sci. USA 104, 20908–20913 (2007).
Acknowledgements
A.A. is the recipient of an Advanced Grant of the European Research Council and is supported by grants from the European Union (PRIORITY, LUPAS), the Swiss National Foundation, the National Competence Center on Neural Plasticity and Repair, the Stammbach Foundation, and the Novartis Research Foundation. J.F. is supported by a grant from the Swiss Center of Transgenic Expertise and by a career development award of the University of Zürich.
Author information
Authors and Affiliations
Contributions
The concepts discussed here were developed by A.A. and discussed with J.F. A.A. and J.F. both wrote the manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Aguzzi, A., Falsig, J. Prion propagation, toxicity and degradation. Nat Neurosci 15, 936–939 (2012). https://doi.org/10.1038/nn.3120
Published:
Issue Date:
DOI: https://doi.org/10.1038/nn.3120
This article is cited by
-
Functional genomics screen identifies proteostasis targets that modulate prion protein (PrP) stability
Cell Stress and Chaperones (2021)
-
PrP is a central player in toxicity mediated by soluble aggregates of neurodegeneration-causing proteins
Acta Neuropathologica (2020)
-
Contribution of syndecans to cellular uptake and fibrillation of α-synuclein and tau
Scientific Reports (2019)
-
Structural and mechanistic aspects influencing the ADAM10-mediated shedding of the prion protein
Molecular Neurodegeneration (2018)
-
Enhanced neuroinvasion by smaller, soluble prions
Acta Neuropathologica Communications (2017)