A prion protein missense variant is integrated in kuru plaque cores in patients with Gerstmann-Straussler syndrome

Spongiform encephalopathies are neurological diseases in which brain tissue takes on the appearance of sponge and affected persons or animals develop severe neurological dysfunction. The search for the causative agent in spongiform encephalopathies has been unrewarding to date, but has examined Creutzfeldt-Jakob disease, kuru, and Gerstmann-Straussler-Scheinker syndrome in humans and scrapie in animals, and has uncovered a peculiar protein that is always found in the brains of affected individuals. This protein, termed prion protein (PrP), is thought by some to be the primary constituent of a particle of infectious protein with little or no DNA or RNA. Prion protein is found in both a normal state and a mutant condition in the diseased state. In the case of Gerstmann-Straussler-Scheinker syndrome, patients were heterozygous for a mutation at codon 102; the normal gene codes for proline at this point, while the mutation codes for leucine. Researchers undertook an effort to determine if this mutation could be demonstrated conclusively in the composition of the kuru-type plaques that are a common pathological finding in cases of spongiform encephalopathy. Since the entire brain is contaminated with prion protein, it was first necessary to purify the plaques themselves; this was accomplished by centrifugation. The protein constituents of the plaques were then enzymatically degraded with a protease that cleaves at lysine. This procedure yielded a series of protein fragments which could be separated using high pressure liquid chromatography (HPLC). While two of the three distinguishable fragments were common to both forms of PrP, the third showed that at least some of the prion protein located in the kuru-like plaques recovered from these brains was the mutant protein. This finding confirms the previous observation of mutant PrP in kuru plaques using immunohistochemical staining techniques. (Consumer Summary produced by Reliance Medical Information, Inc.)