We have generated lines of transgenic mice that express a mutant prion protein containing 14 octapeptide repeats whose human homologue is associated with an inherited prion dementia. These mice develop an ataxic illness that begins at 65 days of age when the transgene array is homozygous, and results in death by 115-138 days. Starting from birth, mutant PrP is converted into a protease-resistant and detergent-insoluble form that resembles PrP(Sc), and this form accumulates dramatically in many brain regions throughout the lifetime of the mice. As PrP accumulates, there is massive apoptosis of cerebellar granule cells, as well as astrocytosis and deposition of PrP in a punctate pattern. These results establish a new transgenic animal model of an inherited human prion disease, and provide important insights into the molecular pathogenesis of these disorders.