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From: TSS (216-119-143-153.ipset23.wt.net)
Subject: RATIONAL TARGETING FOR PRION THERAPEUTICS
Date: December 23, 2004 at 2:29 pm PST
-------- Original Message --------
Subject: RATIONAL TARGETING FOR PRION THERAPEUTICS
Date: Thu, 23 Dec 2004 09:12:13 -0600
From: "Terry S. Singeltary Sr."
Reply-To: Bovine Spongiform Encephalopathy
To: BSE-L@LISTSERV.KALIV.UNI-KARLSRUHE.DE
##################### Bovine Spongiform Encephalopathy #####################
Nature Reviews Neuroscience 6, 23-34 (2005); doi:10.1038/nrn1584 RATIONAL TARGETING FOR PRION THERAPEUTICS
Giovanna Mallucci & John Collinge about the authors
Abstract Prions — pathogens that are lethal to humans and other animals — are
thought to be conformational isomers of the cellular prion protein.
Their unique biology, and the potential for a wider pathobiological
significance of prion-like mechanisms, has motivated much research into
understanding prion neurodegeneration. Moreover, concerns that extensive
dietary exposure to bovine spongiform encephalopathy (BSE) prions might
have infected many individuals — who might eventually develop its human
counterpart, variant Creutzfeldt–Jakob disease (vCJD) — has focused much
interest on therapeutics. The challenge of interrupting this aggressive,
diffuse and uniformly fatal neurodegenerative process is daunting.
However, the recent finding that the onset of clinical disease in
established neuroinvasive prion infection in a mouse model can be halted
and early pathology reversed is a source for considerable optimism. A
therapeutic focus on the cellular prion protein, rather than prions
themselves, which might not be directly neurotoxic, is suggested.
Summary
* Prion diseases, or transmissible spongiform encephalopathies, are
fatal neurodegenerative conditions that affect humans and other
animals, and are transmissible within or between mammalian
species. The recognition in 1996 of a new human prion disease —
variant CreutzfeldtJakob disease (vCJD) — and the experimental
confirmation that it is caused by bovine spongiform encephalopathy
(BSE)-like prions derived from infected beef products have led to
fears of a human epidemic.
* Prion diseases are all associated with the accumulation in the
brain of an abnormal, partially protease-resistant, isoform of
host-encoded prion protein (PrP). The disease-related isoform
(PrPSc) is derived from the normal cellular isoform PrPC by a
post-translational process that involves conformational change and
aggregation. Many studies support the 'protein-only' hypothesis of
prion propagation, according to which an abnormal PrP isoform is
the principal, and possibly the sole, constituent of the
transmissible agent or prion. Therefore, PrPSc is thought to act
as a conformational template, recruiting PrPC to form further PrPSc.
* However, the cause of neuronal death in prion disease remains
unclear. The assumption that neurodegeneration follows from direct
toxicity of PrPSc and/or prions has been increasingly challenged.
Evidence against the direct toxicity of PrPSc is discussed, with
particular reference to the occurrence of sub-clinical forms of
prion infection, in which high levels of PrPSc accumulate in the
absence of neurotoxicity or clinical symptoms, as well as the more
recent demonstration that switching off PrPC expression in mice
with neuroinvasive prion disease results in the reversal of early
spongiform degeneration and long-term survival of animals despite
ongoing non-neuronal PrPSc production.
* Other potential mechanisms of neurotoxicity in prion diseases are
presented, including possible roles for PrPC in cell survival and
cell death signalling pathways and the potential toxicity of
aberrant PrPC processing and trafficking in neurons.
* The concept of the generation of neurotoxic forms of PrP,
designated 'PrPL' (PrP lethal), during prion replication, which
might involve soluble oligomers of misfolded PrP, is emphasized.
The rationale for focussing on therapeutic strategies that target
normal PrPC rather than PrPSc itself, where stabilizing the native
form will prevent the generation of toxic intermediates, is
explained.The balance between the production and clearance of PrPL
(and PrPSc) in prion infection in determining ultimate
neurotoxicity is discussed, with particular relevance for
therapeutic intervention.
* Other therapeutic strategies, including targeting PrPSc and
immunotherapeutic modulation, are considered, as well as potential
future strategies, such as gene silencing by RNA interference and,
ultimately, stem cell therapy for the repair of damaged tissue.
* Consideration is given to human therapeutic studies and the need
for advances in the early diagnosis of prion infection.
http://www.nature.com/cgi-taf/DynaPage.taf?file=/nrn/journal/v6/n1/abs/nrn1584_fs.html&dynoptions=doi1103814629
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