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From: TSS ()
Subject: Insights into prion strains and neurotoxicity
Date: June 25, 2007 at 10:41 am PST

Insights into prion strains and neurotoxicity

Adriano Aguzzi, Mathias Heikenwalder and Magdalini Polymenidou

Abstract |

Transmissible spongiform encephalopathies (TSEs) are neurodegenerative
diseases that are caused by prions and affect humans and many animal species. It is
now widely accepted that the infectious agent that causes TSEs is PrPSc, an aggregated
moiety of the host-derived membrane glycolipoprotein PrPC. Although PrPC is encoded by the
host genome, prions themselves encipher many phenotypic TSE variants, known as
prion strains. Prion strains are TSE isolates that, after inoculation into distinct hosts,
cause disease with consistent characteristics, such as incubation period, distinct patterns of
PrPSc distribution and spongiosis and relative severity of the spongiform changes in the brain.
The existence of such strains poses a fascinating challenge to prion research.


snip...


Prions and public health

Prion infections account for a frightening number of
medical and veterinarian incidents. The bovine spongiform
encephalopathy (BSE) crisis, which ravaged cow herds in
Europe and elsewhere, has been mainly resolved ó at
least in the countries that have implemented serious
epidemiological sentinel systems. Furthermore, the
incidence of vCJD has not risen significantly for several
years (FIG. 1a). However, in the United States of America,
there has been an enigmatic rise of chronic wasting disease
(CWD) in elk and deer19 and the first cases of BSE have
occurred20. Also, there has been a recrudescence of
scrapie outbreaks among European sheep flocks. Because
it is difficult to discriminate between scrapie and BSE
in sheep, it is possible that some cases of alleged sheep
scrapie may be ovine BSE.
Until now, mainly tissues from the central nervous
system (CNS) and lymphoreticular system (LRS) were
regarded as high-risk biologicals. However, recently,
prion infectivity has been observed in inflamed extraneural
non-lymphoid organs of mice21,22 and naturally
scrapie-sick sheep23, as well as in saliva and blood from
CWD and scrapie-diseased animals24,25. Prion infectivity
was also detected in the urine of prion-infected mice
that suffered from nephritis22. These reports indicate that
environmental cofactors (inflammatory and others)
might broaden the distribution of prion infectivity to
many organs and body fluids of prion-affected animals,
and calls into question the current risk assessment of
high-infectivity organs.
So far, four cases of vCJD have been reported to be
caused by blood transfusion26Ė28, which indicates that
BSE prions can be recycled among humans. These
observations caused considerable alarm that the
supply of blood-derived pharmaceuticals might be
threatened29. Because carriers of vCJD with no clinical
symptoms are just as likely to donate blood as any other
uninfected person, it is likely that new cases of bloodborne
prion infections will be witnessed in the future.
Until now, only individ uals who were homozygous for a
polymorphic site in the human PRNP gene (Met/Met at
codon 129) were found to succumb to vCJD. However,
subclinical blood-derived vCJD infection was found
in an individual who was hetero zygous at this site
(129Met/Val)27. This finding suggests that BSE prions,
once circulating within the human population, might
gain virulence and attack a broader range of susceptible
recipients.


snip...


Box 2 | Anti-prion-protein antibodies for anti-prion therapy?

Approximately 5 years ago, several independent studies indicated that
anti-prionprotein (anti-PrP) antibodies can block prion replication both in vitro and in vivo.
In 2001, Enari and Weissmann described how chronically prion-infected cells
were rescued by treatment with antibodies against cellular prion protein
(anti-PrPC)119. Only weeks later, Peretz and colleagues confirmed these results using
antibody fragments directed against specific PrPC domains120. We independently found
that transgenic mice with an antibody repertoire that was skewed towards
recognition of PrPC were protected from scrapie pathogenesis on intraperitoneal prion
inoculation121. Two years later, it was reported that passive transfer of anti-PrP
monoclonal antibodies delays the onset of scrapie in mice infected with prions by the
intraperitoneal route122. The above in vivo studies imply that the prionostatic action of anti-PrP
antibodies occurs in the periphery, that is, before prions reach the central nervous
system. This may be due to the overall limited immunoglobulin influx into the brain, which
has already accumulated a high prion load by the time prion disease reaches the clinical
stages. Much interest has focused on active immunization, with the goal being to
achieve antibody-based anti-prion prophylaxis. Yet, the mammalian immune system is
essentially tolerant to PrPC because it is expressed on the surface of
almost all cells in the body. Nonetheless, following active immunization with a wealth of
PrP-related antigens such as synthetic peptides, recombinant proteins and
brain-extracted PrP, induction of anti-PrP antibodies in wild-type mice has been
described123Ė132. However, in the instances in which they have been evaluated,
the biological efficacy of these immunization series proved to be limited. By characterizing
the immune responses of wild-type and various transgenic
mice, we found that a prerequisite for prophylactic anti-PrP antibodies is the
recognition of cellsurface-
bound PrPC (REF. 133). Even when using virus-like particles, which were
shown to be efficient at overcoming self-tolerance in many cases134, the tolerance
of mice to PrPC was essentially not broken135.
Moreover, antibody-mediated crosslinking of PrPC in vivo was found to
trigger neuronal apoptosis in the brain136. These data, along with the complications
of immunotherapy in other cerebral amyloidoses137, have somewhat dampened the
prospects that antibody-based therapeutic strategies will be useful in
clinical practice in the near future.


snip...


Distinct molecular signatures of BSE. BSE is characterized
by an exclusive and remarkably stable biochemical
profile of PrPSc and, until recently, BSE was believed to
be associated with one single prion strain, sometimes
referred to as classical BSE. However, distinct molecular
signatures have recently been discovered through the
large-scale screening of cattle by European authorities
in the context of BSE surveillance. These atypical profiles
fall into one of two groups: higher (H)-type cases
of protease-resistant fragments with a molecular weight
that is higher than classical BSE, and bovine amyloidotic
spongiform encephalopathy (BASE), or lower
(L)-type69. To test whether these different biochemical
and histopathological properties correspond to distinct
strains, H-type PrPSc isolates from French cattle were
transmitted into transgenic mice that expressed bovine
or ovine PrPC (REF. 70). The recipient mice developed
neurological signs with strain-specific features that were
clearly distinct from those of the classical BSE agent,
thereby providing pivotal evidence that the underlying
strains are distinct.

Do A ‚ strains exist in Alzheimerís disease?

A recent report from the laboratory of Mathias Jucker provided
in vivo evidence that similar phenomena might occur
in Alzheimerís disease (AD)71. Intracerebral injection of
amyloid-‚ (A‚)-containing brain extracts from humans
with AD (or from ‚-amyloid precursor protein (APP)
transgenic mice) induced cerebral ‚-amyloidosis and
associated pathology in APP transgenic mice. These
mice also had disease phenotypes that were determined
by both the host and the inoculum. The authors postulated
the existence of A‚ strains that can initiate and
therefore accelerate aggregation and A‚ pathology.
These observations are intriguing and support the
hypothesis that the pathogenetic mechanisms that
operate in AD and in prion diseases have more in
common than was previously postulated72,73. It remains
to be seen whether different A‚ strains with distinct
biochemical or neuropathological characteristics occur
in humans.


snip...

Figure 4 | Do different PrPSc types in patients with sCJD and vCJD represent
different prion strains? The coexistence of scrapie prion protein (PrPSc)
subtypes was shown by independent studies63,64 in the brains of patients with sporadic
Creutzfeldt-Jakob disease (sCJD) and variant (v)CJD. sCJD type 2 and vCJD type 2b cases
were found to bear small amounts of sCJD type 1 in at least one brain area. In the
future, it will be important to investigate whether these PrPSc subtypes represent different
strains, and whether the coexistence and different ratios of these distinct PrPSc
subtypes influence the lesion profile and clinical history of patients. The boxes indicate the
banding pattern of proteinase-K-digested PrPSc in each case. Each type manifests with a
distinct clinical and neuropathological phenotype. Red indicates the brain areas (cerebellum
and cortex) in which coexistence of the respective PrPSc types was shown63,64.


snip...


Conclusions and future directions

As discussed in this Review, significant progress has
been made in the identification of prion strains and in
understanding the neurotoxicity of prion infections. The
development and appropriate use of tools and technologies
has enabled us to answer some long-standing
key questions; however, many questions are still left
un answered. Our understanding of how the physio logical
PrP converts into an infectious agent is still sketchy at
best. We do not understand how strain information is
maintained and transmitted, and we have no notion of
the mechanisms that define the tropisms of prion strains.
Finally, we do not understand how neurotoxicity is
induced by the prion agent, and why it is less toxic to
cells of the immune system ó where it also undergoes
live replication. These two questions might be related
to the physiological functions of PrPC, which are also
still unclear. Are these functions executed through
interaction with other proteins, and if so, what are these
proteins? Is there a Ďprion entry receptorí in extraneural
cells? And finally, what is the atomic structure of the
prion agent? In view of this list of open questions, it is
clear that prion science has by no means outlived itself.
The unresolved questions do not represent a Ďcleanupí
in the wake of a fundamental discovery but, rather, they
lend themselves to additional important research that
has the potential to make a significant impact on human
medicine and basic science.


full text ;

NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 8 | JULY 2007 | 559
© 2007 Nature Publishing Group www.nature.com/reviews/molcellbio


TSS




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