DIFFERENT PATTERNS OF TRUNCATED PRION PROTEIN-FRAGMENTS CORRELATE WITH DISTINCT PHENOTYPES IN P102L GERSTMANN-STRAUSSLER-SCHEINKER-DISEASE

The clinicopathological phenotype of the Gerstmann-Straussler-Scheinke r disease (GSS) variant linked to the codon 102 mutation in the prion protein (PrP) gene (GSS P102L) shows a high heterogeneity. This variab ility also is observed in subjects with the same prion protein gene PR NP haplotype and is independent from the duration of the disease, Immu noblot analysis of brain homogenates from GSS P102L patients showed tw o major protease-resistant PrP fragments (PrP-res) with molecular mass es of approximate to 21 and 8 kDa, respectively, The 21-kDa fragment, similar to the PrP-res type 1 described in Creutzfeldt-Jakob disease, was found in five of the seven subjects and correlated with the presen ce of spongiform degeneration and ''synaptic'' pattern of PrP depositi on whereas the 8-kDa fragment, similar to those described in other var iants of GSS, was found in all subjects in brain regions showing PrP-p ositive multicentric amyloid deposits. These data further indicate tha t the neuropathology of prion diseases largely depends on the type of PrP-res fragment that forms in vivo. Because the formation of PrP-res fragments of 7-8 kDa with ragged N and C termini is not a feature of C reutzfeldt-Jakob disease or fatal familial insomnia but appears to be shared by most GSS subtypes, it may represent a molecular marker for t his disorder.