Nature 380, 528 - 531 (11 April 1996); doi:10.1038/380528a0

Loss of cerebellar Purkinje cells in aged mice homozygous for a disrupted PrP gene

Suehiro Sakaguchi^*†, Shigeru Katamine, Noriyuki Nishida^*, Ryozo Moriuchi^*, Kazuto Shigematsu^*, Tetsuo Sugimoto^§, Akira Nakatani^*, Yasufumi Kataoka, Takeshi Houtani^§, Susumu Shirabe^¶, Hitoshi Okada^£, Sumitaka Hasegawa^*, Tsutomu Miyamoto^* & Tetsuo Noda^£

^*
Departments of ^* Bacteriology, ^‡ Pathology, Pharmacology, and ^¶ Internal Medicine I, Nagasaki University School of Medicine, 1-12-4 Sakamoto, Nagasaki 852, Japan
^§ Department of Anatomy, Kansai Medical University, Moriguchi 570, Japan
^£ Department of Cell Biology, Cancer Institute, Tokyo 170, Japan
^† Present address: Institut fur Molekularbiologie I, Universitat Zurich, 8093 Zurich, Switzerland.

PRION protein (PrP) is a glycoprotein constitutively expressed on the neuronal cell surface. A protease-resistant isoform of prion protein is implicated in the pathogenesis of a series of transmissible spongiform encephalopathies¹. We have developed a line of mice homozygous for a disrupted PrP gene in which the whole PrP-coding sequence is replaced by a drug-resistant gene². In keeping with previous results^3–8, we find that homozygous loss of the PrP gene has no deleterious effect on the development of these mice and renders them resistant to prion². The PrP-null mice grew normally after birth, but at about 70 weeks of age all began to show progressive symptoms of ataxia. Impaired motor coordination in these ataxic mice was evident in a rotorod test. Pathological examination revealed an extensive loss of Purkinje cells in the vast majority of cerebellar folia, suggesting that PrP plays a role in the long-term survival of Purkinje neurons.

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