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Published Online October 17, 2002
Science DOI: 10.1126/science.1073619

Reports

Submitted on May 6, 2002
Accepted on September 30, 2002

Conversion of PrP to a Self-Perpetuating PrPSc-like Conformation in the Cytosol

Jiyan Ma 1 Susan Lindquist 2*

1 Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, OH 43210, USA; Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA.
2 Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA.

* To whom correspondence should be addressed. E-mail: lindquist_admin{at}wi.mit.edu.

A rare conformation of the prion protein, PrPSc, is found only in mammals with transmissible prion diseases and represents either the infectious agent itself or a major component of it. The mechanism for initiating PrPSc formation is unknown. We report that PrP retrograde-transported out of the endoplasmic reticulum produced both amorphous aggregates and a PrPSc-like conformation in the cytosol. The distribution between these forms correlated with the rate of appearance in the cytosol. Once conversion to the PrPSc-like conformation occurred, it was sustained. Thus, PrP has an inherent capacity to promote its own conformational conversion in mammalian cells. These observations might explain the origin of PrPSc.


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