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Originally published in Science Express on 17 October 2002
Science 29 November 2002:
Vol. 298. no. 5599, pp. 1781 - 1785
DOI: 10.1126/science.1073725
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Reports

Neurotoxicity and Neurodegeneration When PrP Accumulates in the Cytosol

Jiyan Ma,1* Robert Wollmann,2 Susan Lindquist3dagger

Changes in prion protein (PrP) folding are associated with fatal neurodegenerative disorders, but the neurotoxic species is unknown. Like other proteins that traffic through the endoplasmic reticulum, misfolded PrP is retrograde transported to the cytosol for degradation by proteasomes. Accumulation of even small amounts of cytosolic PrP was strongly neurotoxic in cultured cells and transgenic mice. Mice developed normally but acquired severe ataxia, with cerebellar degeneration and gliosis. This establishes a mechanism for converting wild-type PrP to a highly neurotoxic species that is distinct from the self-propagating PrPSc isoform and suggests a potential common framework for seemingly diverse PrP neurodegenerative disorders.

1 Howard Hughes Medical Institute,
2 Department of Pathology, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637, USA.
3 Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Nine Cambridge Center, Cambridge, MA 02142, USA.
*   Present address: Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, OH 43210, USA.

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

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