A protease-resistant 61-residue prion peptide causes neurodegeneration in transgenic mice

An abridged prion protein (PrP) molecule of 106 amino acids, designated PrP 106, is capable of forming infectious miniprions in transgenic mice (S. Sup attapone, 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 s equences from PrP106 and identified a 61-residue peptide, designated PrP61, that spontaneously adopted a protease-resistant conformation in neuroblast oma cells. Synthetic PrP61 bearing a carboxy-terminal lipid moiety polymeri zed into protease resistant, beta -sheet-enriched amyloid fibrils at a phys iological salt concentration. Transgenic mice expressing low levels of PrP6 1 died spontaneously with ataxia. Neuropathological examination revealed ac cumulation of protease resistant PrP61 within neuronal dendrites and cell b odies, apparently causing apoptosis, PrP61 may be a useful model for deciph ering the mechanism by which PrP molecules acquire protease resistance and become neurotoxic.