PSI+
Transcription
PSI+
Prion Buntownik bez (znanego) powodu Takao Ishikawa ! Festiwal Nauki w Warszawie 23 września 2014 r. Co to są białka? Wyraz wprowadzony przez Jönsa J. Berzeliusa w 1883 r. w celu podkreślenia znaczenia tej grupy związków. Termin pochodzi od greckiego słowa proteios, które oznacza “pierwszorzędny”. Białko to liniowa sekwencja aminokwasów połączonych ze sobą wiązaniem peptydowym. Funkcje energetyczne Funkcje komunikacyjne Funkcje mechaniczne i transportowe Funkcje magazynujące i wydalnicze Prion protein: PrP C PrP Sc PrP Cellular Scrapie Nazwa PrP PrP Struktura Dominująca struktura drugorzędowa α-heliks β-kartka Rozpuszczalne w środowisku wodnym Tak Nie Podatne na proteolizę Tak Nie Morfologia Amyloid Barwienie czerwienią Kongo (CR), obserwacja w mikroskopie polaryzacyjnym Ed Uthman, MD, Houston, TX, USA 1. 2. 3. PrPC PrPSc Efekty delecji genu PRNP • Częstsze przerwy snu • Gorsza pamięć krótko- i długoterminowa • Wycofanie • Upośledzenie syntezy otoczki mielinowej • Brak odpowiedzi na MK-801 Steele i wsp. (2007) Prion Oddziaływanie PrP z NR2 Khosravani (2008)inJ.neonatal Cell Biol. alysis of the NMDAR NR2D subunit distribution. (A) Western blot analysis of the NR2D subunit proteini wsp. expression an Neurotoksyczność PrPSc Sc PrP Aβ Resenberger i wsp. (2011) EMBO J. Kamath et al. Page 13 Zespół Alagille Figure 3. Map of the 20p deletions from each of the patients studied. A map of selected genes from 20p is presented along the top, and the extent of the deletions is represented by a line. The dotted lines indicate the boundaries of the “Alagille only” critical region. Deletions that are fully within these boundaries do not appear to be associated with clinical features outside of those seen in Alagille syndrome. Kamath i wsp. (2010) Hum. Mutat. Choroby prionowe • Choroba CreutzfeldtaJakoba (CJD) • Rodzinna śmiertelna bezsenność (FFI) • Zespół GerstmannaSträusslera-Scheinkera (GSS) • Kuru Choroba Creutzfeldta-Jakoba • fCJD (familial) • forma • iCJD dziedziczna (infectious/iatrogenic) zakaźna m.in. z powodu preparatów hormonów wzrostu • forma • vCJD (variant) • infekcja • sCJD prionami bydlęcymi? (spontaneous) • spontaniczna forma choroby ? przed 1720 1986 1947 ? przed 1920 (sCJD) ok. 1960 ok. 1990 1994 (vCJD) www.cdc.gov 7. G. M. McKhann et al., Arch. Neurol. 58, 1803 (2001). ALS corresponds to pathologically hyperphos21 August 2006; accepted 8 September 2006 8. M. Grossman, J. Int. Neuropsychol. Soc. 8, 566 10.1126/science.1134108 (2002). phorylated TDP-43 as in FTLD-U (Fig. 4M). However, the presence of UBIs in ALSby immunohistochemistry in tonsil, brain (medulla oblongata at Fig. 1. because PrPCWD demonstrated cases is more variable than their presence in obex), node of deer receiving saliva or blood from CWD-infected FTLD-U, and not all retropharyngeal brain regions examined inlymph all cases exhibited pathological TDP-43. donors. CWD immunohistochemistry is shown in the medulla at obex (A to H) and either tonsil or These studies identify TDP-43 as the major CWD staining (red) within brain and retropharyngeal lymph node (I to P) (8). Arrows indicate PrP disease protein in the signature UBIs of FTLDU and ALS.follicles. Although pathologically altered lymphoid Arrow with asterisk indicates lymphoid follicle negative for PrPCWD. ^, scale bar 0 TDP-43 proteins were present in all sporadic 550 mm; ^^, scale baras 0ALS 110 mm. and familial FTLD-U as well cases, there were subtle differences in these abnormal TDP-43 variants among the three FTLD-U subtypes, which may be the result of similar but Candace K. Mathiason,1 Jenny G. Powers,3 Sallie J. Dahmes,4 David A. Osborn,5 Karl V. Miller,5 not identical pathogenic mechanisms. The dif- Robert J. Warren,5 Gary L. Mason,1 Sheila A. Hays,1 Jeanette Hayes-Klug,1 Davis M. Seelig,1 ferential distribution of UBIs detected by Margaret A. Wild,3 Lisa L. Wolfe,6 Terry R. Spraker,1,2 Michael W. Miller,6 Christina J. Sigurdson,1 ubiquitin antibodies in FTLD-U subtypes (18) Glenn C. Telling,7 Edward A. Hoover1* supports this view. TDP-43 is a ubiquitously expressed, highly A critical concern in the transmission of prion diseases, including chronic wasting disease (CWD) conserved nuclear protein (24) that may be a of cervids, is the potential presence of prions in body fluids. To address this issue directly, we transcription repressor and an activator of exon exposed cohorts of CWD-naı̈ve deer to saliva, blood, or urine and feces from CWD-positive deer. skipping (21, 25, 26) as well as a scaffold for We found infectious prions capable of transmitting CWD in saliva (by the oral route) and in blood nuclear bodies through interactions with sur(by transfusion). The results help to explain the facile transmission of CWD among cervids and vival motor neuron protein (27). TDP-43 is prompt caution concerning contact with body fluids in prion infections. normally localized primarily to the nucleus, but our data indicate that, under pathological conditions in FTLD-U, TDP-43 is eliminated from he prion diseases, or transmissible insoluble partially protease-resistant isoform nuclei of UBI-bearing neurons, a consequence spongiform encephalopathies (TSEs), are (PrPres). CWD, a transmissible spongiform of which may be a loss of TDP-43 nuclear funcchronic, degenerative, neurological dis- encephalopathy of cervids (deer, elk, and tions. Moreover, nuclear UBIs are rare in spo- eases with uniformly fatal outcomes. TSEs are moose), was first observed in the 1960s in radic FTLD-U because most pathological TDP-43 characterized by the conversion of the normal captive deer and free-ranging deer and elk accumulates in neuronal cell bodies or their cellular prion protein (PrPc) to an aberrant in northeastern Colorado and southeastern Fig. 2. Immunoblot demonstration of PrPCWD in brain (medulla) of white-tailed deer. (A) PrPCWD Infectious Prions in the Saliva and Blood of Deer with Chronic Wasting Disease T detection in positive and negative control deer (8). Lane demonstrates the expected molecular weight www.sciencemag.org SCIENCE VOL3314 6 OCTOBER 2006 133 shift upon partial proteinase K (PK) digestion of PrPCWD in CWDþ deer, whereas lane 5 shows the complete digestion of PrPc in CWD-negative deer. Molecular weight markers are indicated in lane 1. (B) Assay for PrPCWD in medulla at obex homogenates for deer inoculated with blood, urine and feces, Prions Adhere to Soil Minerals and Remain Infectious Christopher J. Johnson1,2, Kristen E. Phillips3, Peter T. Schramm3, Debbie McKenzie2, Judd M. Aiken1,2, Joel A. Pedersen3,4* 1 Program in Cellular and Molecular Biology, University of Wisconsin Madison, Madison, Wisconsin, United States of America, 2 Department of Animal Health and Biomedical Sciences, School of Veterinary Medicine, University of Wisconsin Madison, Madison, Wisconsin, United States of America, 3 Molecular and Environmental Toxicology Center, University of Wisconsin Madison, Madison, Wisconsin, United States of America, 4 Department of Soil Science, University of Wisconsin Madison, Madison, Wisconsin, United States of America An unidentified environmental reservoir of infectivity contributes to the natural transmission of prion diseases (transmissible spongiform encephalopathies [TSEs]) in sheep, deer, and elk. Prion infectivity may enter soil environments via shedding from diseased animals and decomposition of infected carcasses. Burial of TSE-infected cattle, sheep, and deer as a means of disposal has resulted in unintentional introduction of prions into subsurface environments. We examined the potential for soil to serve as a TSE reservoir by studying the interaction of the diseaseassociated prion protein (PrPSc) with common soil minerals. In this study, we demonstrated substantial PrPSc adsorption to two clay minerals, quartz, and four whole soil samples. We quantified the PrPSc-binding capacities of each mineral. Furthermore, we observed that PrPSc desorbed from montmorillonite clay was cleaved at an N-terminal site and the interaction between PrPSc and Mte was strong, making desorption of the protein difficult. Despite cleavage and avid binding, PrPSc bound to Mte remained infectious. Results from our study suggest that PrPSc released into soil environments may be preserved in a bioavailable form, perpetuating prion disease epizootics and exposing 1,2 other speciesJ. to the infectious agent. Christopher Johnson , Joel A. Pedersen3, Rick J. Chappell4, Debbie McKenzie2, Judd M. Aiken1,2* Oral Transmissibility of Prion Disease Is Enhanced by Binding to Soil Particles Citation: Johnson CJ, Phillips KE, Schramm PT, McKenzie JM, et al. (2006)Madison, Prions adhere to soilUnited minerals and of remain infectious. PLoS Pathog 2(4): e32. DOI: 10.1371/ 1 Program in Cellular and Molecular Biology, UniversityD, ofAiken Wisconsin-Madison, Wisconsin, States America, 2 Department of Comparative Biosciences, journal.ppat.0020032 School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America, 3 Department of Soil Science and Molecular and Environmental Toxicology Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America, 4 Biostatistics and Medical Informatics, University of Wisconsin Medical School, Madison, Wisconsin, United States of America demonstrated by the recent detection in Colorado, USA, of a Introduction free-ranging, CWD-infected moose, a species not previously Transmissible spongiform encephalopathies prion Soil may serve as an environmental reservoir (TSEs, for prion infectivity andtocontribute the known be affectedtoby thehorizontal disease intransmission the wild [9]. of prion diseases) a group of fatal neurodegenerative diseases that diseasesare (transmissible spongiform encephalopathies [TSEs]) ofAlthough sheep, deer, elk. of TSEenvironmental infectivity cantransmission persist in soil otherand modes of for years, and we that thebovine disease-associated of thebeen prion protein binds to soil particles affect a variety of previously mammaliandemonstrated species and include scrapie andform CWD have proposed flesh flies [10], hay Johnson i wsp. (2006;(e.g., 2007), PLoS pathogens Intranasal Inoculation of White-Tailed Deer (Odocoileus virginianus) with Lyophilized Chronic Wasting Disease Prion Particulate Complexed to Montmorillonite Clay Montmorillonit Montmorillon Tracy A. Nichols1*, Terry R. Spraker2,3, Tara D. Rigg1, Crystal Meyerett-Reid3, Clare Hoover3, Brady Michel3, Jifeng Bian3, Edward Hoover3, Thomas Gidlewski1, Aru Balachandran5, Katherine O’Rourke6¤, Glenn C. Telling3, Richard Bowen4, Mark D. Zabel3., Kurt C. VerCauteren1. 1 National Wildlife Research Center, US Department of Agriculture, Animal and Plant Health Inspection Service, Wildlife Services, Fort Collins, Colorado, United States of America, 2 Colorado State University Diagnostic Laboratory, Fort Collins, Colorado, United States of America, 3 Prion Research Center and the Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University Prion Research Center, Fort Collins, Colorado, United States of America, 4 Department of Biomedical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado, United States of America, 5 National and OIE Reference Laboratory for scrapie and chronic wasting disease, Canadian Food Inspection Agency, Ottawa, Ontario, Canada, 6 U. S. Department of Agriculture, Agricultural Research Service, Pullman, Washington, United States of America Abstract Chronic wasting disease (CWD), the only known prion disease endemic in wildlife, is a persistent problem in both wild and captive North American cervid populations. This disease continues to spread and cases are found in new areas each year. Indirect transmission can occur via the environment and is thought to occur by the oral and/or intranasal route. Oral transmission has been experimentally demonstrated and although intranasal transmission has been postulated, it has not been tested in a natural host until recently. Prions have been shown to adsorb strongly to clay particles and upon oral inoculation the prion/clay combination exhibits increased infectivity in rodent models. Deer and elk undoubtedly and chronically inhale dust particles routinely while living in the landscape while foraging and rutting. We therefore hypothesized that dust represents a viable vehicle for intranasal CWD prion exposure. To test this hypothesis, CWD-positive brain homogenate was mixed with montmorillonite clay (Mte), lyophilized, pulverized and Nichols inoculated intranasally i wsp. (2013)into PLoS ONE • • • Mocznik GuHCl SDS Microbiol Immunol 2010; 54: 112–121 doi:10.1111/j.1348-0421.2009.00190.x ORIGINAL ARTICLE A novel anti-prion protein monoclonal antibody and its single-chain fragment variable derivative with ability to inhibit abnormal prion protein accumulation in cultured cells Yoshihisa Shimizu1 , Yuko Kaku-Ushiki2 , Yoshifumi Iwamaru1 , Tamaki Muramoto3 , Tetsuyuki Kitamoto3 , Takashi Yokoyama1 , Shirou Mohri1 and Yuichi Tagawa4 1 Prion Disease Research Center, National Institute of Animal Health, 3-1-5 Kannondai, Tsukuba, Ibaraki 305-0856, 2 Nippi Research Institute of Biomatrix, 520-11 Kuwabara, Toride, Ibaraki 302-0017, 3 Department of Prion Research, Tohoku University Graduate School of Medicine, 2-1 Seiryou-machi, Aoba-ku, Sendai, Miyagi 980-8575, and 4 National Institute of Animal Health, 3-1-5 Kannondai Tsukuba, Ibaraki 305-0856, Japan ABSTRACT mAbs T1 and T2 were established by immunizing PrP gene ablated mice with recombinant MoPrP of residues 121–231. Both mAbs were cross-reactive with PrP from hamster, sheep, cattle and deer. A linear epitope of mAb T1 was identified at residues 137–143 of MoPrP and buried in PrPC expressed on the cell surface. mAb T1 showed no inhibitory effect on accumulation of PrPSc in cultured scrapie-infected neuroblastoma (ScN2a) cells. In contrast, mAb T2 recognized a discontinuous epitope ranged on, or structured by, residues 132–217 and this epitope was exposed on the cell surface PrPC . mAb T2 showed an excellent inhibitory effect on PrPSc accumulation in vitro at a 50% inhibitory concentration of 0.02 µg/ml (0.14 nM). The scFv form of mAb T2 (scFv T2) was secreted in neuroblastoma (N2a58) cell cultures by transfection through eukaryotic secretion vector. Coculturing of ScN2a cells with scFv T2-producing Quinacrine • Hamuje polimeryzację PrPSc • Brak aktywności in vivo • Problem pokonania bariery krew-mózg? ue was 3.14 lg/mL, although that of PSK-Sug was the survival period of prion-infected animals. The Contents lists at ScienceDirect g/mL. To further study the active components ofavailablenism of the PrPres formation is still enigmatic, bu yzed PSK-Pro using Sephacryl S-200 HR gel filtraPrPc molecules, which mainly localize in the l Biochemical and Biophysical that Research Communications aphy. PSK-Pro showed a single sharp peak around domain of the cell membrane, are altered to PrP ed with silver staining after SDS–PAGE, with PrPres molecules j o u r n a l hwhich o m e p a gwas e : w w w . e l sthrough e v i e r . c o m / direct l o c a t e / y binteraction brc on-2 (Supplementary Fig. 1C, Fig. 3C). This high far, it has been demonstrated that lactoferrin [20] a t fraction sample of PSK-Pro had strong inhibitory of anti-PrP monoclonal antibodies [21] inhibit PrPr he PrPres formation in ScN2a cells (Fig. 3D). The affecting the turnover. PSK, however, neither a Anti-prion activity of protein-bound polysaccharide K inPrPc prion-infected cells hat a ca. 150 kDa-sized protein-related substance or cell surface PrPc levels nor modified the localiz and animals n anti-prion component(s) of PSK. the lipid raft microdomain. This suggests that Taichi Hamanaka a, Yuji Sakasegawa a, Akihiro Ohmoto a, Tomohiro Kimura a, Takao Ando b, Katsumi Doh-ura a,⇑ a b Department of Neurochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan Biomedical Research Laboratory, Kureha, Co. Ltd., 3-26-2 Hyakunin-cho, Shinjuku-ku, Tokyo 169-8503, Japan a r t i c l e i n f o Article history: Received 31 December 2010 Available online 8 January 2011 Keywords: Prion Prion-infected cells Protein-bound polysaccharide K Immunotherapeutic agent a b s t r a c t Protein-bound polysaccharide K (PSK) is a clinical immunotherapeutic agent that exhibits various biological activities, including anti-tumor and anti-microbial effects. In the present study, we report on the anti-prion activity of PSK. It inhibited the formation of protease-resistant abnormal prion protein in prion-infected cells without any apparent alterations in either the normal prion protein turnover or the autophagic function in the cells. Its anti-prion activity was predominantly composed of the high molecular weight component(s) of the protein portion of PSK. A single subcutaneous dose of PSK slightly but significantly prolonged the survival time of peritoneally prion-infected mice, but PSK-treated mice produced neutralizing antibodies against the anti-prion activity of PSK. These findings suggest that PSK is a new anti-prion substance that may be useful in elucidating the mechanism of prion replication, although the structure of the anti-prion component(s) of PSK requires further evaluation. ! 2011 Elsevier Inc. All rights reserved. Wrośniak 1. Introductionróżnobarwny Transmissible spongiform encephalopathies or prion diseases include Creutzfeldt–Jakob disease (CJD), Gerstmann–Sträussler– Scheinker syndrome, and familial fatal insomnia in humans. All of these diseases are fatal and characterized by the accumulation of protease-resistant abnormal prion protein, prion, in the brain infected cells and animals, and we discuss the mechanism of its prion-inhibitory activity. PSK is known to be effective in conjunction with chemotherapy and/or radiotherapy for some types of cancers through various immunological modulations [7], and also has anti-microbial activities [8], but this is the first time that its anti-prion activity has been revealed. Strategie leczenia chorób prionowych • Stabilizacja złogów amyloidowych • Rozdrabnianie złogów amyloidowych do monomerów PrP • Wśród leków na inne amyloidozy • Poszukiwania w naturze Czy buntownik może być jedynie szkodliwy dla otoczenia? #$%&'()* ! 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"#/ 4#5),).#.' .2' '+%,-.)%( %4 ('3 .&#).19 ?=4 >@AB8 C;D;:7E @6F;G;6F;68 A;6;8@< <B76A;C =<<9: @6 <=6<;:8 8= G:=F9<; 7 6;4 H=:> =: H96<8@=6I )6; C=E98@=6 @C 8= G=C@8 8B; ;J@C8;6<; =H >;<B76@C>C 8B78 7EE=4 <B76A;C 8= 7<<9>9E78; @6 7 8B; E=CC =H 8B; G:@=6 76F :;C8=:78@=6 =H 8:76CE78@=67E QF;E@8KL/5 #B; G:@=6SF;8;:>@6@6A :;A@=6 =H 09GVX B7C R;;6 :;87@6;F @6 F@C8768EK :;E78;F K;7C8.,W.VP @6F@<78@6A 8B78 8B; 969C97E 7R@E@8K =H 09GVX 8= Prion [PSI+] 10-6 10-6 curing 10-6 fenotyp wt 10-4 fenotyp mutanta dysruptant ≈ WicknerWickner i wsp., 2007 i wsp. (2007) Prion the s are on of Istota prionu [PSI+] [psi-], Sup35p in normal state STOP [PSI+], Sup35p in prion state STOP STOP mRNA Protein Soluble Sup35p Aggregated Ribosome Stop codon Sup35p Ishikawa (2008) Mycoscience Fenotyp [PSI+] [PSI+] [psi-] konwersja Benomyl Bleomycyna Anisomycyna związek grzybobójczy lek na nowotwory inhibitor syntezy białek [PSI+] [psi-] Wickner wsp.,(2000) 2007 True iiLindquist Nature Środowisko sprzyjające [psi-] Nagła zmiana warunków Środowisko sprzyjające [PSI+] Powrót do środowiska pierwotnego Powrót do środowiska pierwotnego Susan Lindquist “A yeast prion provides a mechanism for genetic variation and phenotypic diversity” True i Lindquist (2000) Nature Reed Wickner “Yeast prions [URE3] and [PSI+] are diseases” Nakayashiki i wsp. (2005) PNAS A Systematic Survey Identifies Prions and Illuminates Sequence Features of Prionogenic Proteins Simon Alberti,1,5 Randal Halfmann,1,3,5 Oliver King,1,4 Atul Kapila,1,3 and Susan Lindquist1,2,3,* 1Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA 2Howard Hughes Medical Institute, Cambridge, MA 02139, USA 3Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA 4Boston Biomedical Research Institute, Watertown, MA 02472, USA 5These authors contributed equally to this work *Correspondence: [email protected] DOI 10.1016/j.cell.2009.02.044 SUMMARY Prions are proteins that convert between structurally and functionally distinct states, one or more of which is transmissible. In yeast, this ability allows them to capacity have been discovered (Shorter and Du et al., 2008). Most of these have been f S. cerevisiae, with the [PSI+] element being the [PSI+] is caused by an amyloid-like aggre translation-termination factor Sup35p. In th majority of Sup35p molecules are inactive, res Pełno prionów! Alberti i wsp. (2009) Cell Pełno prionów! Prion Domains Form Intracellular Aggregates Detectable by Microscopy and SDD-AGE Alberti i wsp. (2009) Cell (Drożdżowe) priony (chyba) pełnią (jakąś) rolę Jarosz i wsp. (2014a; 2014b) Cell Buntownik nadzieją Lamarcka? UW zbm bm.. www.biol.uw.edu.pl/zbm/takao