A kiss of a prion: new implications for oral transmissibility.
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ABSTRACT: Neurodegenerative diseases are caused by proteinaceous aggregates, usually consisting of misfolded proteins which are often typified by a high proportion of β-sheets, which accumulate in the Central Nervous System. These diseases, including Morbus Alzheimer, Parkinson disease and Transmissible Spongiform Encephalopathies (TSEs)--also termed prion disorders--afflict a substantial proportion of the human population and as such the etiology and pathogenesis of these diseases has been the focus of mounting research. Although many of these diseases arise from genetic mutations or are sporadic in nature, the possible horizontal transmissibility of neurodegenerative diseases poses a great threat to population health. In this article we discuss recent studies which suggest that the "non-transmissible" status bestowed upon Alzheimer and Parkinson diseases may need to be revised as these diseases have been successfully induced through tissue transplants. Furthermore, we highlight the importance of investigating the "natural" mechanism of prion transmission including peroral and perenteral transmission, proposed routes of gastrointestinal uptake and neuroinvasion of ingested infectious prion proteins. We examine the multitude of factors which may influence oral transmissibility and discuss the zoonotic threats which Chronic Wasting Disease (CWD), Bovine Spongiform Encephalopathy (BSE) and Scrapie may pose resulting in vCJD or related disorders. In addition, we suggest that the 37 kDa/67 kDa laminin receptor on the cell surface of enterocytes, a major cell population in the intestine, may play an important role in the intestinal pathophysiology of alimentary prion infections.Prion 01/2011; 5(1):6-9. · 1.97 Impact Factor
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ABSTRACT: Amyloid β (Aβ) is a major causative agent of Alzheime disease. This neurotoxic peptide is generated as a result of the cleavage of the Amyloid-Precursor-Protein (APP) by the action of beta secretase and gamma secretase. The neurotoxicity was previously thought to be the result of aggregation. However, recent studies suggest that the interaction of Aβ with numerous cell surface receptors such as N-methyl-D-aspartate (NMDA), receptor for advanced glycosylation end products (RAGE), P75 neurotrophin receptor (P75NTR) as well as cell surface proteins such as the cellular prion protein (PrP(c) ) and heparan sulfate proteoglycans (HSPG) strongly enhances Aβ induced apoptosis and thereby contributes to neurotoxicity. This review focuses on the molecular mechanism resulting in Aβ-shedding as well as Aβ-induced apoptotic processes, genetic risk factors for familial Alzheimer disease and interactions of Aβ with cell surface receptors and proteins, with particular emphasis on the cellular prion protein. Furthermore, comparisons are drawn between Alzheimer disease and prion disorders and the role of laminin, an extracellular matrix protein, glycosaminoglycans and the 37 kDa/67 kDa laminin receptor (LRP/LR) have been highlighted with regards to both neurodegenerative diseases.Prion 07/2011; 5(3):126-37. · 1.97 Impact Factor
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ABSTRACT: The prion protein is a glycoprotein characterized by a folded α-helical structure that, under pathological conditions, misfolds and aggregates into its infectious isoform as β-sheet rich amyloidic deposits. The accumulation of the abnormal protein is responsible for a group of progressive and fatal disorders characterized by vacuolation, gliosis, and spongiform degeneration. Prion disorders are characterized by a triple aetiology: familial, sporadic or acquired, although most cases are sporadic. The mechanisms underlying prion neurotoxicity remain controversial, while novel findings lead to hypothesize intriguing pathways responsible for prion spreading. The present review aims to examine the involvement of the gastrointestinal tract and hypothesizes the potential mechanisms underlying cell-to-cell transmission of the prion protein. In particular, a special emphasis is posed on the mechanisms of prion transmission within the gut and towards the central nervous system. The glycation of prion protein to form advanced glycation end-products (AGE) interacting with specific receptors placed on neighboring cells (RAGE) represents the key hypothesis to be discussed.Prion 07/2011; 5(3):142-9. · 1.97 Impact Factor
• JID 2010:201 (1 June) • 1615
E D I T O R I A L C O M M E N TA R Y
A Kiss of a Prion: New Implications for Oral Transmissibility
Bianca Da Costa Dias and Stefan F. T. Weiss
School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg, South Africa.
(See the report by Maddison et al, on pages 1672–1676.)
Received 11 February 2010; accepted 23 February 2010;
electronically published 19 April 2010.
Potential conflicts of interest: none reported.
Financial support: Deutsche Forschungsgemeinschaft, Germany
Reprints or correspondence: Prof Stefan F. T. Weiss, School
of Molecular and Cell Biology, University of the Witwatersrand,
Private Bag 3, 2050 Wits, Johannesburg, South Africa (stefan
The Journal of Infectious Diseases
? 2010 by the Infectious Diseases Society of America. All
There is no doubt about it: prions—in-
fectious particles composed mainly if not
entirely of misfolded protein (scrapie-type
prion protein [PrPSc]), which arethecaus-
ative agents of transmissible spongiform
encephalopathies (TSE) such as scrapie,
variant Creutzfeldt-Jakob Disease (vCJD),
and bovine spongiform encephalopathy
(BSE)—are transmissible [1–3]. These
agents may be introduced via intracere-
bral, intravenous, intraperitoneal, or in-
traventricular infection, and recent re-
search indicates that oral transmission
may also occur. The last mode of trans-
mission is of particular interest because it
indicates that the consumption of meat
and other products derived from animals
experiencing prion disorders may pose a
that, in addition to meat, bodily fluids
such as blood, saliva, feces, and milk may
well be risk factors for possible transmis-
sion of TSEs to humans. Successful oral
transmission among different animal spe-
cies (interspecies) has been demonstrat-
ed. However, species specificity, the “spe-
cies barrier,” and the mode of transmis-
sion must be taken into account and may
explain why cattle, sheep, goats, mink,
and mice are successfully orally infected
with bovine scrapie-type prion protein
(bovPrPSc), whereas the ingestion of
bovPrPScby pigs, poultry, and cervids
such as elk and deer fails to cause disease
. Humans are also thought to be sus-
ceptible to oral infection by bovPrPScby
means of contaminated bovine products
(eg, meat pies), and this is believed to be
the manner in which the zoonotic disease
vCJD originated .
But where do prions hide in the body?
vous system, particularly in the brain and
the lymphoreticular system , as well as
in other tissues such as muscle . Fur-
thermore, the presence of these infec-
tious agents in bodily excretions and se-
cretions is a major cause for concern,
because it enhances the risks of trans-
missibility. Prions have been identified in
feces of asymptomatic deer  and in the
blood, saliva, and urine of deer with
chronic wasting disease [7, 8]. PrPSchas
also been detected in the salivary glands
of scrapie-affected sheep .
The report by Maddison et al  in
this issue of the Journal describes for the
first time, to our knowledge, the secretion
of prions into the oral cavityofsheep.The
centrate prions, in conjunction with serial
protein misfolding cyclic amplification, or
sPMCA, a method to amplify and detect
the presence of very low concentrationsof
PrPSc. Serial protein misfolding cyclic am-
plification has numerous applications,
such as the sensitive detection of patho-
logical prions , later application for in
vitro generation of prions , and de-
tection of prions in body fluids such as
blood from scrapie-infected hamsters
; the last example succeeded even in
et al  used this technique to demon-
strate that prions are present in buccal
swab samples obtained from sheep with
preclinical scrapie infections.
However, one must pose the following
question: how do ingested infectiousPrPSc
prions reach the mucus and saliva? After
oral ingestion, prions are thought to be
taken up first by Peyer patchesbeforethey
disseminate through gut-associated lym-
phoid tissues, the lymphoreticular system,
the vagus nerve, and the enteric nervous
system, after which they enter the central
nervous system . Internalization of
prions in the intestine is thought to be
performed by M-(microfold) cells 
and by enterocytes, which internalize
bovPrPScdependent on the prion receptor
Maddison et al  suggest, according
to their data, that prions areabletospread
glands and epithelia within a period of 9
months. This route explains the occur-
rence of prions in saliva and the shedding
of prions into the oral cavity.
The transmissibility of scrapie among
sheep (intraspecies) is well recognized. It
must be emphasized thathorizontaltrans-
fer (from one individual to another) of
scrapie is the main route of infection, be-
mother to offspring via milk or placental
tissue occurs infrequently. Thus, in view
of the report by Maddison et al, the oral
transmissibility of prions among sheep
at University of Witwatersrand on April 10, 2014
1616 • JID 2010:201 (1 June) • EDITORIAL COMMENTARY
may serve as a major route for horizontal
scrapie transfer. This occurrence is plau-
sible because sheep often lick each other.
Maddison et al  indicate that, because
of the similarities in prion tissue distri-
bution, their implications for the oral
transmission of ovine scrapie might be
true for other prion diseases, such as cer-
vid chronic wasting disease and human
vCJD. If this is true for humans, a kiss of
a prion may sometimes have lethal
We thank the Deutsche Forschungsgemein-
schaft (DFG) grant WE 2664/2–1, Germany and
the National Research Foundation (NRF), South
Africa, for financial support. We thank Professor
Juergen Richt, Kansas State University, United
States, for a critical reading of this paper.
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at University of Witwatersrand on April 10, 2014