PHENOTYPIC VARIABILITY OF GERSTMANN-STRAUSSLER-SCHEINKER-DISEASE IS ASSOCIATED WITH PRION PROTEIN HETEROGENEITY

Gerstmann-Straussler-Scheinker disease (GSS), a cerebello-pyramidal sy ndrome associated with dementia and caused by mutations in the prion p rotein gene (PRNP), is phenotypically heterogeneous. The molecular mec hanisms responsible for such heterogeneity are unknown. Since we hypot hesize that prion protein (PrP) heterogeneity may be associated with c linico-pathologic heterogeneity, the aim of this study was to analyze PrP in several GSS variants. Among the pathologic phenotypes of GSS, w e recognize those without and with marked spongiform degeneration. In the latter (i.e. a subset of GSS P102L patients) we observed 3 major p roteinase-K resistant PrP (PrPres) isoforms of ca. 21-30 kDa, similar to those seen in Creutzfeldt-Jakob disease. In contrast, the 21-30 kDa isoforms were not prominent in GSS variants without spongiform change s, including GSS A117V, GSS D202N, GSS Q212P, GSS Q217R, and 2 cases o f GSS P102L. This suggests that spongiform changes in GSS are related to the presence of high levels of these distinct 21-30 kDa isoforms. V ariable amounts of smaller, distinct PrPres isoforms of ca. 7-15 kDa w ere seen in all GSS variants. This suggests that GSS is characterized by the presence PrP isoforms that can be partially cleaved to low mole cular weight PrPres peptides.