A transgenic model of a familial prion disease

We have generated lines of transgenic mice that express a mutant prion prot ein containing 14 octapeptide repeats whose human homologue is associated w ith an inherited prion dementia. These mice develop an ataxic illness that begins at 65 days of age when the transgene array is homozygous, and result s in death by 115-138 days. Starting from birth. mutant PrP is converted in to a protease-resistant and detergent-insoluble form that resembles PrPSc, and this form accumulates dramatically in many brain regions throughout the lifetime of the mice. As PrP accumulates, there is massive apoptosis of ce rebellar 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 m olecular pathogenesis of these disorders.