The Prion Protein in Health and Disease

C. Weissmann, D. Shmerling, I. Hegy1, A. Cozzio, E. Flechsig, M. Fischer, C. Holtz, T. Blättler1, S. Brandner1, J. Götz, T. Rülicke2, A. Aguzzi1

Institut für Molekularbiologie, Abteilung I, Universität Zürich, 8093 Zürich; 1Institut für Neuropathologie; 2Biologisches Zentrallabor, Universitätspital, Zürich 8001, Switzerland

The transmissible agent that causes spongiform encephalopathies such as BSE or scrapie, the prion, is believed to be devoid of nucleic acid and identical with PrP*, a modified form of the normal host protein PrPC which is found predominantly on the surface of neurons. The "protein-only" hypothesis proposes that Pr*, when introduced into a healthy host, multiplies by causing conversion of PrPC into PrP*. Prusiner proposed that a protease-resistant form of PrP, PrPSc, which accumulates intracellularly in scrapie-infected organisms is PrP*; while this identification is still uncertain, much evidence supports the idea that the infectious agent consists of a conformationally altered form of PrP devoid of nucleic acid.

The physiological function of the cellular prion protein PrP is still unknown. We have produced PrP knockout (Prnpo/o) mice and found them to develop and behave normally. As predicted by the "protein-only" hypothesis, they are resistant to scrapie and do not propagate scrapie agent. Surprisingly, heterozygous Prnpo/+ mice, which express PrPC at about half the normal level, lived for over a year without clinical symptoms, despite high levels of infectious agent and PrPSc in the brain early on.

Prnpo/o mice that overexpress mini-transgenes encoding full-length PrP regain susceptibility to scrapie. We generated transgenic Prnpo/o mice expressing PrP with amino-proximal deletions. Removal of amino acids 32 to 93 (comprising the five octarepeats) did not affect normal behaviour and still enabled susceptibility to scrapie. However, deletions to amino acid 121 or 134 (which remove the unstructured domain of PrP) led to severe ataxia and neuronal death restricted to the granule layer of the cerebellum, 1-2 months after birth. This disease was not transmissible. The defect was abolished by crossing in a single wild-type PrP allele. We propose that in wild-type mice, PrP interacts with a conjectural ligand to elicit a signal and that this signal can also result from the interaction of the ligand with a presumed PrP-like protein p. This would explain why ablation of PrP gives no obvious phenotype. We postulate that truncated PrP can interact with the ligand without giving rise to a signal and competes efficiently with p, thus acting as an inhibitor of the latter.