Primary myopathy and accumulation of PrPSc-like molecules in peripheral tissues of transgenic mice expressing a prion protein insertional mutation

A nine-octapeptide insertional mutation in the prion protein (PrP) gene is associated with an inherited variant of Creutzfeldt-Jakob disease in humans . Transgenic mice that express the mouse PrP homologue of this mutation (de signated PG14) under control of a PrP promoter display a progressive neurol ogical disorder characterized by ataxia, apoptosis of cerebellar granule ce lls, and accumulation in the brain of mutant PrP molecules that display the biochemical hallmarks of PrPSc, the pathogenic isoform of PrP. In this rep ort, we have investigated the expression of PG14 PrP in the peripheral tiss ues of these mice. We found highest levels of mutant PrP in the brain and s pinal cord, intermediate levels in skeletal muscle, heart, and testis and l ow levels in kidney, lung, spleen, intestine, and stomach. Up to 70% of the PG14 PrP expressed in peripheral tissues was detergent-insoluble, and dige stion with low concentrations of proteinase K yielded a PrP 27-30 fragment. These results suggest that the mutant protein was converted to a physical state reminiscent of PrPSc, although its infectivity remains to be determin ed. Histological analysis of skeletal muscle, one of the peripheral tissues with the highest level of PG14 PrP, revealed features indicative of a prog ressive, primary myopathy, including central nuclei, necrotic and regenerat ing fibers, and variable fiber size. These results indicate that the PG14 m utation structurally alters the protein in a way that promotes conversion t o a PrPSc-like state, regardless of the tissue context, and suggest that ac cumulation of PrPSc can have deleterious effects on skeletal muscle cells a s well as on neurons. (C) 2001 Academic Press.