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

Abstract

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, β-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.

ACKNOWLEDGMENTS

We thank Chris Petromilli, Conny Heinrich, Darlene Groth, and Patrick Culhane for their expert contributions.

This work was supported by grants from the National Institutes of Health (NS14069, AG02132, and AG10770) and the American Health Assistance Foundation as well as a gift from the Leila and Harold Mathers Foundation. Surachai Supattapone was supported by the Burroughs Wellcome Fund Career Development Award and an NIH Clinical Investigator Development Award (K08 NS02048-02). Mass spectrometry was carried out in the UCSF Mass Spectrometry Facility, supported by NIH NCRR RR01614.