DEGENERATION OF SKELETAL-MUSCLE, PERIPHERAL-NERVES, AND THE CENTRAL-NERVOUS-SYSTEM IN TRANSGENIC MICE OVEREXPRESSING WILD-TYPE PRION PROTEINS

Prion diseases of humans and animals are known to be caused by infecti on with prions containing PrP(Sc) or mutation of the prion protein (Pr P) gene. During transgenetic studies, we discovered that uninoculated older mice harboring high copy numbers of wild-type (wt) PrP transgene s derived from Syrian hamsters (SHa), sheep (She), and PrP-B mice deve loped truncal ataxia, hindlimb paralysis, and tremors. These transgeni c (Tg) mice exhibited a profound necrotizing myopathy involving skelet al muscle, a demyelinating polyneuropathy, and focal vacuolation of th e central nervous system. Development of disease was dependent on tran sgene dosage. For example, half of all Tg(SHaPrP+/+)7 mice homozygous for the SHaPrP transgene array developed disease by approximately 460 days of age, while no hemizygous Tg(SHaPrP+/0)7 mice became ill before 650 days. The novel neurologic syndrome found in older Tg(wtPrP) mice implies that overexpression of wtPrP(C) is pathogenic and widens the spectrum of prion diseases.