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Molecular and Cellular Biology, April 2001, p. 2608-2616, Vol. 21, No. 7
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.7.2608-2616.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

A Protease-Resistant 61-Residue Prion Peptide Causes Neurodegeneration in Transgenic Mice

Surachai Supattapone,1,2 Essia Bouzamondo,3 Haydn L. Ball,1,2 Holger Wille,1,2 Hoang-Oanh B. Nguyen,1,2 Fred E. Cohen,1,4,5,6 Stephen J. DeArmond,1,3 Stanley B. Prusiner,1,2,6 and Michael Scott1,2,*

Institute for Neurodegenerative Diseases1 and Departments of Neurology,2 Pathology,3 Cellular and Molecular Pharmacology,4 Medicine,5 and Biochemistry and Biophysics,6 University of California at San Francisco, San Francisco, California 94143

Received 29 September 2000/Returned for modification 1 December 2000/Accepted 18 December 2000

An abridged prion protein (PrP) molecule of 106 amino acids, designated PrP106, is capable of forming infectious miniprions in transgenic mice (S. Supattapone, P. Bosque, T. Muramoto, H. Wille, C. Aagaard, D. Peretz, H.-O. B. Nguyen, C. Heinrich, M. Torchia, J. Safar, F. E. Cohen, S. J. DeArmond, S. B. Prusiner, and M. Scott, Cell 96:869-878, 1999). We removed additional sequences from PrP106 and identified a 61-residue peptide, designated PrP61, that spontaneously adopted a protease-resistant conformation in neuroblastoma cells. Synthetic PrP61 bearing a carboxy-terminal lipid moiety polymerized into protease-resistant, beta -sheet-enriched amyloid fibrils at a physiological salt concentration. Transgenic mice expressing low levels of PrP61 died spontaneously with ataxia. Neuropathological examination revealed accumulation of protease-resistant PrP61 within neuronal dendrites and cell bodies, apparently causing apoptosis. PrP61 may be a useful model for deciphering the mechanism by which PrP molecules acquire protease resistance and become neurotoxic.

* Corresponding author. Mailing address: Institute for Neurodegenerative Diseases, Box 0518, University of California, San Francisco, CA 94143-0518. Phone: (415) 476-4482. Fax: (415) 476-8386.

Molecular and Cellular Biology, April 2001, p. 2608-2616, Vol. 21, No. 7
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.7.2608-2616.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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