September 2011

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A neurotoxic mechanism of some special PrP mutants. Qi Shi and ... mutants outside this region (P102L and E200K) in cells do not produce detectable CtmPrP ...
Editor-in-Chief Yury O. Chernoff Department of Biology Georgia Institute of Technology Atlanta, GA, USA

Volume 5 • Issue 3 • July/August/September 2011 Associate Editor Galina Zhouravleva

Editorial Board Adriano Aguzzi Jason C. Bartz Janine Beisson Bernd Bukau Neil R. Cashman Byron Caughey Brian S. Cox Christophe Cullin Douglas M. Cyr Chris Dobson Pascale Dupuis-Williams Pierluigi Gambetti Bernardino Ghetti John Glover David A. Harris Sergey Inge-Vechtomov Jeffrey W. Kelly Liming Li Pawel P. Liberski Susan Liebman Susan Lindquist David G. Lynn Yoshikazu Nakamura Kevin F. O'Connell Annalisa Pastore Stanley Prusiner Richard A. Rachubinski Sven J. Saupe Hermann M. Schätzl Michael Y. Sherman Greenfield Sluder M. Catia Sorgato Claudio Soto Witold K. Surewicz Glenn C. Telling Michael D. Ter-Avanesyan Mick F. Tuite Erich E. Wanker Stefan F.T. Weiss Charles Weissmann Jonathan Weissman Reed B. Wickner

Volu m e 5 I ssu e 3 J u ly /A ugust /S e p t e mbe r 2011 E ditor - i n -C hi e f

Y u ry C h e r nof f G e orgi a I ns t i t u t e of Tech nol ogy A t l a n ta , GA USA

REVIEWS 123 CtmPrP and ER stress: A neurotoxic mechanism of some special PrP mutants Qi Shi and Xiao-Ping Dong

About the cover TDP-43 and FUS are two RNAbinding proteins with prion domains that have been associated with neurodegenerative diseases ALS and FTLD-U. In a Commentary, Aaron Gitler and James Shorter describe recent results using yeast models and in vitro biochemistry to define mechanisms of aggregation and toxicity. Cover design by Lili Guo (www.lilyscientificart.com). For additional information, see Gitler et al., pp. 179–87.

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Structural and mechanistic commonalities of amyloid-b and the prion protein Bianca Da Costa Dias, Katarina Jovanovic, Danielle Gonsalves and Stefan F.T. Weiss

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COMMENTARIES & VIEWS Aerosols: An underestimated vehicle for transmission of prion diseases? Lothar Stitz and Adriano Aguzzi

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Transmission of prions within the gut and toward the central nervous system Gianfranco Natale, Michela Ferrucci, Gloria Lazzeri, Antonio Paparelli and Francesco Fornai

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Real-time quaking-induced conversion: A highly sensitive assay for prion detection Ryuichiro Atarashi, Kazunori Sano, Katsuya Satoh and Noriyuki Nishida

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Genome wide association studies and prion disease Ana Lukic and Simon Mead

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The p75NTR extracellular domain: A potential molecule regulating the solubility and removal of amyloid-b Xin-Fu Zhou and Yan-Jiang Wang

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The sensitive [SWI+] prion: New perspectives on yeast prion diversity Justin K. Hines and Elizabeth A. Craig

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Prion protein in ESC regulation Alberto Miranda, Eva Pericuesta, Miguel Ángel Ramírez and Alfonso Gutiérrez-Adán

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Insoluble cellular prion protein and its association with prion and Alzheimer diseases Wen-Quan Zou, Xiaochen Zhou, Jue Yuan and Xiangzhu Xiao

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RNA-binding proteins with prion-like domains in ALS and FTLD-U Aaron D. Gitler and James Shorter

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RESEARCH PAPERS Comparative analysis of essential collective dynamics and NMR-derived flexibility profiles in evolutionarily diverse prion proteins Kolattukudy P. Santo, Mark Berjanskii, David S. Wishart and Maria Stepanova

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Can prion disease suspicion be supported earlier? Clinical, radiological and laboratory findings in a series of cases Alejandra González-Duarte, Zaira Medina, Rainier Rodriguez Balaguer and Jesus Higuera Calleja

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Site-specific structural analysis of a yeast prion strain with species-specific seeding activity Anna Marie Marcelino-Cruz, Moumita Bhattacharya, Aaron C. Anselmo and Peter M. Tessier

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Early behavioral changes and quantitative analysis of neuropathological features in murine prion disease: Stereological analysis in the albino Swiss mice model Roseane Borner, João Bento-Torres, Diego R.V. Souza, Danyelle B. Sadala, Nonata Trevia, José Augusto Farias, Nara Lins, Aline Passos, Amanda Quintairos, José Antônio Diniz, Victor Hugh Perry, Pedro Fernando Vasconcelos, Colm Cunningham and Cristovam W. Picanço-Diniz

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SHORT COMMUNICATIONS Allelic frequency and genotypes of prion protein at codon 136 and 171 in Iranian Ghezel sheep breeds Siamak Salami, Reza Ashrafi Zadeh, Mir Davood Omrani, Fatemeh Ramezani and Amir Amniattalab

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The first Chinese case of Creutzfeldt-Jakob disease patient with R208H mutation in PRNP Cao Chen, Qi Shi, Chan Tian, Qing Li, Wei Zhou, Chen Gao, Jun Han, and Xiao-Ping Dong

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ERRATUM Erratum to: Generation of antisera to purified prions in lipid rafts Robert Hnasko, Ana V. Serban, George Carlson, Stanley B. Prusiner and Larry H. Stanker

Abstracted/Indexed in Medline/PubMed, Index Medicus and Scopus. Print ISSN: 1933-6896; Online ISSN: 1933-690X

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REVIEW

REVIEW

Prion 5:3, 123-125; July/August/September 2011; © 2011 Landes Bioscience

PrP and ER stress

Ctm

A neurotoxic mechanism of some special PrP mutants Qi Shi and Xiao-Ping Dong* State Key Laboratory for Infectious Disease Prevention and Control; National Institute for Viral Disease Control and Prevention; Chinese Center for Disease Control and Prevention; Beijing, China

Key words: prion, CtmPrP, ER stress, transmembrane region, mutant

The pathogenic agent is hypothesized to be PrPSc in prion diseases. However, little accumulation of PrPSc is repeatedly observed in some kinds of natural and experimental prion diseases, including some special genetic human prion diseases. One of the specific topology forms of PrP, Ctm PrP, representing a key neurotoxic intermediate in prion disorders, has been testified in cell-free translation systems and transgenic mice models. Recently, some studies have showed that point-mutations within the hydrophobic transmembrane region increase the amount of CtmPrP in cells, such as human homologue A117V which is associated with GSS and G114V associated with gCJD, while the mutations outsides transmembrane region do not. The retention of the CtmPrP in ER subsequently is able to induce ER stress and apoptosis, which is supported by upregulation of ER chaperone synthesis, such as Grp78, Grp58, Grp94, Bip and the transcription factor CHOP/ GADD153. In conclusion, some kinds of intermediate forms of PrPSc, including CtmPrP, may work as the ultimate cause of neurodegeneration.

Introduction Prion diseases or transmissible spongiform encephalopathies (TSE) are a group of neurodegenerative diseases, including Creutzfeldt-Jacob disease (CJD), Gerstmann-SträusslerScheinker syndrome (GSS), fatal familial insomnia (FFI) and Kuru in humans, scrapie in sheep and bovine spongiform encephalopathy (BSE) in cattle.1 The pathogenic agent is hypothesized to be PrPSc, an abnormal isoform that is infectious in the absence of nucleic acid and is converted from PrPC, a normal cell-surface glycoprotein. The secondary structural difference between two PrP isoforms seems to be clear that PrPSc contains significantly more β-sheet structure.2 Although deposits of PrPSc in brains are common pathological features of prion diseases, significant pathology and clinical dysfunction with little accumulation of PrPSc are repeatedly observed in some kinds of natural and experimental prion diseases.3 Hence, the infectious form of PrP may not be the proximate cause of neuronal dysfunction and degeneration. Several alternative forms of PrP have therefore *Correspondence to: Xiao-Ping Dong; Email: [email protected] Submitted: 05/02/11; Accepted: 07/07/11 DOI: 10.4161/pri.5.3.16327

been hypothesized to be the primary neurotoxic species designated PrPtoxic, such as CtmPrP.4 Approximately 10–15% of human prion cases are related with the mutations of prion protein gene (PRNP) on chromosome 20, which form a special subtype of human prion diseases or CJD, including genetic or familial CJD (gCJD or fCJD), GerstmannSträussler-Scheinker syndrome (GSS) and fatal familial insomnia (FFI).5 More than 55 mutations in PRNP have been confirmed to be associated with or directly linked to the development of genetic human prion diseases.6 The mutations consist of a series of insertions or deletion of octarepeats in the N-terminus of PrP and numerous point-mutations in the middle and C-terminal sequences of PrP. Interestingly, the pathological characteristics and clinical phenotypes vary largely among various gCJDs, which strongly highlights that different mutated PrP forms may have distinct pathologic pathways. Ctm

PrP, One of the Membrane Topology Forms of PrP

Most mature PrP molecules present on the surface of cells through their GPI anchors that serve as their sole means of attachment to the lipid bilayer after post-translational modification processes in endoplasmic reticulum (ER) lumen and Golgi apparatus.7 Additionally, PrP contains a conserved hydrophobic sequence that can span the lipid bilayer in either direction, resulting in two transmembrane forms, designated CtmPrP and NtmPrP. CtmPrP is believed to span the membrane once, with its highly conserved hydrophobic region in the center of the molecule (aa 111–134) as a transmembrane anchor and the C terminus in the ER lumen. Ntm PrP spans the membrane with the same transmembrane segment, but with its N terminus in the ER lumen reversely.8 PrP, a Neurotoxic Element in Some Prion Neurodegeneration Ctm

Presence of several topological forms of PrP, which is firstly noticed in cell-free translation/translocation systems, has been observed for long time.9,10 In the past years, expressions of CtmPrP in experimental rodents have been confirmed to be associated with neurodegenerative diseases. In the transgenic mice expressing PrP molecules carrying mutations within or near the transmembrane domain, obvious CtmPrP can be identified in brain membranes.11 More interestingly, transgenic mice expressing such CtmPrPfavoring mutations are more likely to develop a spontaneous

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neurodegenerative illness that bears some similarities to scrapie and some kinds of human genetic prion diseases, without detectable PrPSc in brains.4,8 Unlike the natural PrPSc, CtmPrP inducing neurodegenerative diseases show extremely low infectivity.12 Although the exact pathogenic role of CtmPrP in prion diseases still remains unclear, numerous data have illustrated that this special molecule possesses significant neurotoxicity. Moreover, Hegde et al. have reported that accumulation of PrPSc induces an enhanced generation of CtmPrP, implying that CtmPrP represents a key neurotoxic intermediate in prion disorders.4 Ctm

PrP, a Trigger for ER Stress and Apoptosis

Many cell biological assays highlight that CtmPrP contains an uncleaved signal peptide as well as a GPI anchor, which retains intracellularly in either the ER or the Golgi depending on the cell type.13 An ER stress and subsequent apoptosis has been repeatedly observed in the cells of retention of the abnormal CtmPrP in ER, which is believed to be the normal physiological reaction for cleaning out the misfolding proteins.14 Supporting this claim, many protective molecular chaperons, such as GRP78, GRP94, GRP29, ORP150, PDI, SERCA, HO-1, SERP1 and Herp, are obviously upregulated due to the ER stress.15 Normally, the unfolded protein response (UPR) could results in upregulation of ER chaperone synthesis, such as Grp78, Grp58, Grp94 and Bip, which are adaptive in nature, but the induction of the transcription factor CHOP/GADD153 and phosphorylation of the translation initiation factor eIF-2 can damage cells by triggering apoptosis.16,17 More recently, Wang et al. have proposed the evidences that enhanced levels of ER stress up-stream proteins Grp78, Grp58, PERK and Bip are specifically observed in the cells, after formation of CtmPrP by expressions of either the genetic engineering recombinant PrPs retained in ER (PrPKDEL and PrP-3AV) or the genetic prion disease associated PrP mutants within the transmembrane region (PrP-G114V and PrPA117V).18 Subsequently, the presences of the ER stress chaperones trigger the increase of the following apoptosis chaperones such as CHOP and pro-caspase-12. Ctm

PrP, a Cytolic PrP Special in Some PrP Mutants

Up to now, dozens of PrP mutants are definitely confirmed to be related with the prion diseases in humans, either familiarly or spontaneously. Additionally, numerous artificially modified PrP molecules possess the abilities to cause neurodegenerative disorders in transgenic mice. Isaac et al. have classified the PrP mutants into three categories,19 in which the second category of mutations are those in the N-terminal signal sequence and hydrophobic domain that influence the membrane topology of PrP. Wang et al. have illustrated that disease-related point-mutations within References 1. Prusiner SB. Prions. Proc Natl Acad Sci USA 1998; 95:13363-83. 2. Harris DA. Cellular biology of prion diseases. Clin Microbiol Rev 1999; 12:429-44. 3. Telling GC. Transgenic mouse models of prion diseases. Methods Mol Biol 2008; 459:249-63.

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the hydrophobic transmembrane region increase the amount of Ctm PrP in cells, such as human homologue A117V which is associated with GSS20 and G114V associated with gCJD.21 Meanwhile, the formation of CtmPrP in cells seems to be special to the mutations in this region, since expressions of other fCJD-related PrP mutants outside this region (P102L and E200K) in cells do not produce detectable CtmPrP, though those two mutants cause clearly cytotoxicity.18 Besides the transmembrane region, nonconservative substitutions in the core of the N-terminal signal sequence are also able to increase the proportion of CtmPrP, combining these mutations with ones in the central domain results in almost exclusive synthesis of the CtmPrP.22 The inserted mutation of fourteen octarepeats (PrP-PG14) seems to be localized in ER, which induce TSE-like disease after introducing into transgenic mice.23 More recently, Xu et al. propose the data that expressions of the insertions with nine-(PrP-PG9) and twelve-(PrP-PG12) octarepeats partially retain in ER, sensitize the transfected cells to ER stress stimuli and trigger the apoptosis via ER stress, whereas PrP mutant with octarepeats deletion (PrP-PG0) induce apoptosis probably through mitochondrial disruption pathway.24 It lays out a broad diversity of PrP mutations in damaging cells and in resulting in various clinical phenotypes of genetic human TSEs. Speculation PrPSc is found in the brains in most cases of infectious, familial and sporadic prion disease. Although close correlation between the accumulation of PrPSc and the appearance of neuropathological changes have been addressed in most human and animal TSEs, there are still a number of exceptions. Either in some transmission bioassays25 or in some human genetic prion diseases,26 remarkable pathological changes and clinical manifestations are accompanied little deposit of PrPSc in central nerve system. It raises the question whether PrPSc is really the proximate cause for neuron damage in all prion diseases. Partially in line with the phenomenon, the famous peptide PrP106-126 shows rapid toxicity, but almost loses its cytotoxicity after aggregation on the cultured cells,27 possibly indicating a similar manner that the aggregated PrPSc might be nontoxic. Instead of that, some kinds of intermediates, including CtmPrP, may work as the ultimate cause of neurodegeneration. Acknowledgments

This work was supported by Chinese National Natural Science Foundation Grants 30800975, National Basic Research Program of China (973 Program) (2007CB310505), China Mega-Project for Infectious Disease (2009ZX10004-101 and 2008ZX10004008) and the SKLID Development Grant (2008SKLID102, 2011SKLID204 and 2011SKLID211).

4. Hegde RS, Tremblay P, Groth D, DeArmond SJ, Prusiner SB, Lingappa VR. Transmissible and genetic prion diseases share a common pathway of neurodegeneration. Nature 1999; 402:822-6. 5. Kovács GG, Trabattoni G, Hainfellner JA, Ironside JW, Knight RS, Budka H. Mutations of the prion protein gene phenotypic spectrum. J Neurol 2002; 249:1567-82.

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6. Rodriguez MM, Peoc’h K, Haïk S, Bouchet C, Vernengo L, Mañana G, et al. A novel mutation (G114V) in the prion protein gene in a family with inherited prion disease. Neurology 2005; 64:1455-7. 7. Baldwin MA. Analysis of glycosylphosphatidylinositol protein anchors: the prion protein. Methods Enzymol 2005; 405:172-87.

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8. Hegde RS, Mastrianni JA, Scott MR, DeFea KA, Tremblay P, Torchia M, et al. A transmembrane form of the prion protein in neurodegenerative disease. Science 1998; 279:827-34. 9. Lopez CD, Yost CS, Prusiner SB, Myers RM, Lingappa VR. Unusual topogenic sequence directs prion protein biogenesis. Science 1990; 248:226-9. 10. Yost CS, Lopez CD, Prusiner SB, Myers RM, Lingappa VR. Non-hydrophobic extracytoplasmic determinant of stop transfer in the prion protein. Nature 1990; 343:669-72. 11. Stewart RS, Harris DA. Mutational analysis of topological determinants in prion protein (PrP) and measurement of transmembrane and cytosolic PrP during prion infection. J Biol Chem 2003; 278:45960-8. 12. Tateishi J, Kitamoto T, Hoque MZ, Furukawa H. Experimental transmission of Creutzfeldt-Jakob disease and related diseases to rodents. Neurology 1996; 46:532-7. 13. Stewart RS, Piccardo P, Ghetti B, Harris DA. Neurodegenerative illness in transgenic mice expressing a transmembrane form of the prion protein. J Neurosci 2005; 25:3469-77. 14. Harris DA. Trafficking, turnover and membrane topology of PrP. Br Med Bull 2003; 66:71-85. 15. Paschen W. Endoplasmic reticulum dysfunction in brain pathology: critical role of protein synthesis. Curr Neurovasc Res 2004; 1:173-81.

16. Kaufman RJ. Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev 1999; 13:1211-33. 17. Averous J, Bruhat A, Jousse C, Carraro V, Thiel G, Fafournoux P. Induction of CHOP expression by amino acid limitation requires both ATF4 expression and ATF2 phosphorylation. J Biol Chem 2004; 279:5288-97. 18. Wang X, Shi Q, Xu K, Gao C, Chen C, Li XL, et al. Familial CJD associated PrP mutants within transmembrane region induced Ctm-PrP retention in ER and triggered apoptosis by ER stress in SH-SY5Y cells. PLoS One 2011; 6:14602. 19. Lutz J, Brabeck C, Niemann HH, Kloz U, Korth C, Lingappa VR, et al. Microdeletions within the hydrophobic core region of cellular prion protein alter its topology and metabolism. Biochem Biophys Res Commun 2010; 393:439-44. 20. Piccardo P, Liepnieks JJ, William A, Dlouhy SR, Farlow MR, Young K, et al. Prion proteins with different conformations accumulate in Gerstmann-SträusslerScheinker disease caused by A117V and F198S mutations. Am J Pathol 2001; 158:2201-7. 21. Ye J, Han J, Shi Q, Zhang BY, Wang GR, Tian C, et al. Human prion disease with a G114V mutation and epidemiological studies in a Chinese family: a case series. J Med Case Reports 2008; 2:331.

22. Stewart RS, Harris DA. Mutational analysis of topological determinants in prion protein (PrP) and measurement of transmembrane and cytosolic PrP during prion infection. J Biol Chem 2003; 278:45960-8. 23. Biasini E, Medrano AZ, Thellung S, Chiesa R, Harris DA. Multiple biochemical similarities between infectious and non-infectious aggregates of a prion protein carrying an octapeptide insertion. J Neurochem 2008; 104:1293-308. 24. Xu K, Wang X, Shi Q, Chen C, Tian C, Li XL, et al. Human prion protein mutants with deleted and inserted octarepeats undergo different pathways to trigger cell apoptosis. J Mol Neurosci 2011; 43:225-34. 25. Flechsig E, Shmerling D, Hegyi I, Raeber AJ, Fischer M, Cozzio A, et al. Prion protein devoid of the octapeptide repeat region restores susceptibility to scrapie in PrP knockout mice. Neuron 2000; 27:399-408. 26. Tateishi J, Kitamoto T, Kretzschmar H, Mehraein P. Immunhistological evaluation of Creutzfeldt-Jakob disease with reference to the type PrPres deposition. Clin Neuropathol 1996; 15:358-60. 27. Liu YH, Han YL, Song J, Wang Y, Jing YY, Shi Q, Tian C, et al. Heat shock protein 104 inhibited the fibrillization of prion peptide 106–126 and disassembled prion peptide 106–126 fibrils in vitro. Int J Biochem Cell Biol 2011; 43:768-74.

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