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From: TSS (216-119-143-72.ipset23.wt.net)
Subject: Autocatalytic self-propagation of misfolded prion protein 'Our study scrutinizes this hypothesis'
Date: August 17, 2004 at 7:35 pm PST

-------- Original Message --------
Subject: Autocatalytic self-propagation of misfolded prion protein
Date: Tue, 17 Aug 2004 21:37:23 -0500
From: "Terry S. Singeltary Sr."
To: Bovine Spongiform Encephalopathy
CC: cjdvoice@yahoogroups.com


Published online before print August 5, 2004, 10.1073/pnas.0404650101
PNAS | August 17, 2004 | vol. 101 | no. 33 | 12207-12211

Autocatalytic self-propagation of misfolded prion protein

Jan Bieschke *, {dagger} , Petra Weber *, Nikolaus Sarafoff *, Michael
Beekes {ddagger} , Armin Giese * and Hans Kretzschmar *

*Center for Neuropathology and Prion Research, Ludwig Maximilians
University of Munich, Feodor-Lynen-Strasse 23, 81377 Munich, Germany;
and {ddagger} Robert Koch Institute, Nordufer 20, 13353 Berlin, Germany

Communicated by Manfred Eigen, Max Planck Institute for Biophysical
Chemistry, Göttingen, Germany, June 30, 2004 (received for review March
1, 2004)

Prions are thought to replicate in an autocatalytic process that
converts cellular prion protein (PrPC) to the disease-associated
misfolded PrP isoform (PrPSc). Our study scrutinizes this hypothesis by
in vitro protein misfolding cyclic amplification (PMCA). In serial
transmission PMCA experiments, PrPSc was inoculated into healthy hamster
brain homogenate containing PrPC. Misfolded PrP was amplified by rounds
of sonication and incubation and reinoculated into fresh brain
homogenate every 10 PMCA rounds. The amplification depended on PrPC
substrate and could be inhibited by recombinant hamster PrP. In serial
dilution experiments, newly formed misfolded and proteinase K-resistant
PrP (PrPres) catalyzed the structural conversion of PrPC as efficiently
as PrPSc from brain of scrapie (263K)-infected hamsters, yielding an
{approx} 300-fold total amplification of PrPres after 100 rounds, which
confirms an autocatalytic PrP-misfolding cascade as postulated by the
prion hypothesis. PrPres formation was not paralleled by replication of
biological infectivity, which appears to require factors additional to
PrP-misfolding autocatalysis.

------------------------------------------------------------------------
Abbreviations: PMCA, protein misfolding cyclic amplification; PrP, prion
protein; PrpC, cellular PrP; PrPSc, scrapie-associated PrP isoform;
PrPres, proteinase K-resistant PrP; LD50i.c., 50% intracerebral lethal
dose; rPrP, recombinant PrP; SHa, Syrian hamster.

{dagger} To whom correspondence should be sent at the present address:
The Scripps Research Institute, BCC 265, 10550 North Torrey Pines Road,
La Jolla, CA 92037. E-mail: jbiesch@scripps.edu
.

© 2004 by The National Academy of Sciences
of the USA

http://www.pnas.org/cgi/content/abstract/101/33/12207?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=prion&searchid=1092795682466_476&stored_search=&FIRSTINDEX=0&volume=101&issue=33

TSS





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