Increased expression of the normal cellular isoform of prion protein in inclusion-body myositis, inflammatory myopathies and denervation atrophy

The cellular isoform of the prion protein (PrPc) is a glycosylphosphatidyli nositol-anchored glycoprotein, normally expressed in neural and non-neural tissues, including skeletal muscle. In transmissible spongiform encephalopa thies, or prion diseases, PrPc, which is soluble in nondenaturing detergent and sensitive to proteinase K (PK)-treatment, represents the molecular sub strate for the production of a detergent-insoluble and PK-resistant isoform , termed PrPSc. In human prion diseases, PrPSc accumulation occurs only in brain tissues, w ith the exception of new variant Creutzfeldt-Jakob disease, where PrPSSc is also detected in lymphoid tissues. Increased amounts of prion protein expression and deposition have been desc ribed in pathological muscle fibers of two human muscle disorders, called s poradic inclusion-body myositis (s-IBM) and hereditary inclusion-body myopa thy, but it is unknown whether accumulated prion protein reflects normal Pr Pc or PrPSc. We investigated the biochemical characteristics of prion protein in normal human muscle, s-IBM, other inflammatory myopathies and denervation atrophy. We report that 1) both the glycoform profile and size of the normal muscle PrPc are different from those of human brain PrPc; 2) in addition to s-IBM, increased PrPc expression is seen in polymyositis, dermatomyositis and neu rogenic muscle atrophy, but PrPc glycoforms are unchanged; 3) only the norm al PrPc isoform, and not PrPSc, is detected in s-IBM. The present results exclude that s-IBM is a prion disease.