LOSS OF CEREBELLAR PURKINJE-CELLS IN AGED MICE HOMOZYGOUS FOR A DISRUPTED PRP GENE

PRION protein (PrP) is a glycoprotein constitutively expressed on the neuronal cell surface. A protease-resistant isoform of prion protein i s implicated in the pathogenesis of a series of transmissible spongifo rm encephalopathies(1). We have developed a line of mice homozygous fo r a disrupted PrP gene in which the whole PrP-coding sequence is repla ced by a drug-resistant gene(2). In keeping with pre,ious results(3-8) , we find that homozygous loss of the PrP gene has no deleterious effe ct on the development of these mice and renders them resistant to prio n(2). The PrP-null mice grew normally after birth, but at about 70 wee ks of age all began to show progressive symptoms of ataxia. Impaired m otor 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.