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Conformational Conversion and Prion Disease CORRESPONDENCE LINK TO ORIGINAL ARTICLE LINK TO AUTHOR’S REPLY the pathogenesis of prion diseases may be obtained from studies on non-mammalian Conformational conversion and prion prions14,15, as non-mammals also express PrP-encoding genes but do not develop disease prion diseases. Liang Shen and Hong-Fang Ji are at the Shandong Liang Shen and Hong-Fang Ji Provincial Research Center for Bioinformatic Engineering and Technique, Shandong University of Because of mechanistic similarities between gene encoding PrP has been deleted, do Technology, Zibo 255049, China. prion propagation in mammals and fungi, not develop an overt phenotype other than Correspondence to Hong-Fang Ji 5–7 Tuite and Serio recently proposed (The resistance to prion diseases . Thus, it seems e‑mail: [email protected] prion hypothesis: from biological anomaly unlikely that prion pathogenesis is simply doi:10.1038/nrm3007-c1 to basic regulatory mechanism. Nature Rev. due to a loss of PrPC physiological function. 1 C 1. Tuite, M. K. & Serio, T. R. The prion hypothesis: from Mol. Cell Biol. 11, 823–833 (2010)) that In contrast to loss of function of PrP , biological anomaly to basic regulatory mechanism. similarly to fungal prions, which are thought many studies suggest that toxic gain of func‑ Nature Rev. Mol. Cell Biol. 11, 823–833 (2010). Sc 2. Prusiner, S. B. Novel proteinaceous infectious particles to act as phenotype regulators, prions in tion of PrP gives rise to the pathogenic fea‑ cause scrapie. Science 216, 136–144 (1982). mammals should be considered as a basic tures of prion diseases8–10. It has been proven 3. Aguzzi, A. & Polymenidou, M. Mammalian prion Sc biology: one century of evolving concepts. Cell 116, regulatory mechanism instead of a biologi‑ that the accumulation of PrP is linked to 313–327 (2004). cal anomaly. However, by considering the apoptotic cell death in animal models and in 4. Wickner, R. B., Edskes, H. K., Shewmaker, F. & 8 Nakayashiki, T. Prions of fungi: inherited structures behaviour of prions, we argue that the fact humans , and a PrP peptide (PrP106–126) has and biological roles. Nature Rev. Microbiol. 5, that mammalian and fungal prions use a been shown to be neurotoxic to hippocam‑ 611–618 (2007). 5. Büeler H. et al. Normal development and behavior of similar mechanism of conformational con‑ pal cultures, mixed cerebellar cultures and mice lacking the neuronal cell-surface PrP protein. version is not enough to suggest that they are primary neuronal cultures9,10. Some attempts Nature 356, 577–582 (1992). 6. Büeler, H. et al. Mice devoid of PrP are resistant to not just infectious agents. to determine the infectious properties of scrapie, Cell 73, 1339–1347 (1993). Conformational conversion of a protein aggregates produced in vitro from recom‑ 7. Mallucci, G. R. et al. Postnatal knockout of prion Sc protein alters hippocampal CA1 properties, but does from an α‑helix to a β‑strand is usually asso‑ binant PrP found that PrP infectivity was not result in neurodegeneration. EMBO J. 21, ciated with a major change in the tertiary obtained de novo from recombinant mouse 202–210 (2002). C 8. Gray, F. et al. Neuronal apoptosis in Creutzfeldt-Jakob structure, which may alter its physiological PrP (PrP89–230), as shown by transmission disease. J. Neuropathol. Exp. Neurol. 58, 321–328 C 11 (1999). function and even be implicated in severe studies to transgenic mice PrP (PrP89–231) . C 9. Piccardo, P. et al. An antibody raised against a diseases. Prion diseases in mammals are one More recently, recombinant PrP converted conserved sequence of the prion protein recognizes such example; they are caused by the confor‑ into a cross‑β-sheet amyloid was proven to pathological isoforms in human and animal prion 12 diseases, including Creutzfeldt-Jakob disease and mational conversion of normal cellular prion induce prion diseases in hamsters . Unlike bovine spongiform encephalopathy. Am. J. Pathol. protein (PrPC) into an abnormal isoform mammalian prions, the conformational 152, 1415–1420 (1998). Sc 2,3 10. Brown, D. R., Schmidt, B. & Kretzschmar, H. A. (PrP ) . Some fungal proteins can, like conversion of fungal prions does not cause Role of microglia and host protein in neurotoxicity of a prions, also exist in a range of stable confor‑ diseases but instead modifies the functions prion protein fragment. Nature 380, 345–347 (1996). mations and transition between these states of their protein determinants in a self-sus‑ 11. Legname, G. et al. Synthetic mammalian prions. under physiological conditions4; thus, this taining way1, implying that no toxic products Science 305, 673–676 (2004). 12. Makarava, N. et al. Recombinant prion protein type of protein is known as a fungal prion. are generated in this process. In addition, the induces a new transmissible prion disease in First, the conformational conversions of conformational conversion does not seem to wild-type animals. Acta Neuropathol. 119, 177–187 C Sc (2010). PrP to PrP in mammals may result in two be specific to prions, as proteins that adopt 13. Andreeva, A. & Murzin, A. G. Evolution of protein fold outcomes: loss of function of PrPC different secondary structures under differ‑ in the presence of functional constraints. Curr. Opin. Sc C Struct. Biol. 16, 399–408 (2006). and/or gain of toxicity of PrP . If PrP plays ent conditions have not been shown to be 14. Ji, H. F., Zhang, H. Y. & Chen, L. L. Why are prion an important part in the regulatory pathways associated with disease13. This indicates that diseases precluded by non-mammals? Trends Biochem. Sci. 32, 206–208 (2007). that control cellular phenotypes, similarly conformational conversion is not intrinsi‑ 15. Ji, H. F. & Zhang, H. Y. β‑sheet constitution of prion to fungal prions, loss of its function as a cally relevant to the occurrence of diseases. proteins. Trends Biochem. Sci. 35, 129–134 (2010). Sc result of conversion to PrP should lead to In summary, owing to lack of PrP homo‑ Acknowledgements the development of neuropathological and logues in fungi, a conclusion on the potential The authors’ work is supported by the National Natural Science phenotypic alterations that are similar to role of mammalian prions cannot be drawn Foundation of China (grants 30700113 and 30800184). those seen in mammals with prion diseases. merely based on their mechanistic similar­ Competing interests statement However, PrP-knockout mice, in which the ities to fungal prions. More clues regarding The authors declare no competing financial interests. NATURE REVIEWS | MOLECULAR CELL BIOLOGY www.nature.com/reviews/molcellbio © 2011 Macmillan Publishers Limited. All rights reserved.
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