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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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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