Vergleichende Analyse der Gerstmann-Straeussler-Scheinker-Syndrom-assoziierten Mutation A117V mit der neuen pathogenen Mutation G114V des humanen Prion-Proteins in vivo und in vitro
b'Besides its fully translocated form, the prion protein (PrP) can exist in two transmembrane forms (NtmPrP and CtmPrP), which span the lipid bilayer in either direction. Certain mutations in the membrane-spanning segment of PrP have been shown to increase synthesis of CtmPrP and result in neurodegeneration. One of these mutations is A117V, which is associated with Gerstmann-Str\\xe4ussler-Scheinker syndrome (GSS). Sequence-analysis of patients showing neurological disorders revealed a new point-mutation (G114V) in the central region of PrP. The age of affected individuals is strikingly low; the clinical symptoms overlap with GSS as well as Creutzfeldt-Jakob disease. Due to their close vicinity within the transmembrane domain of PrP and misincorporation of valine in both cases, PrP G114V and PrP A117V were investigated in comparative studies. Both mutations caused a similar cellular phenotype strongly differing from wild type PrP. Characteristics included reduced expression of surface PrP as well as increased intracellular accumulation. Besides differences in the cellular localization, a slowed-down metabolism resulting in prolonged transit to the cell surface was detectable. Long-term expression of mutant PrP caused strong agglutination and decline of human neuroblastoma cells that might be due to the increased synthesis of transmembrane forms of mutant PrPs as verified using a cell-free topology assay. When proteasomal degradation was perturbed, PrP G114V and PrP A117V revealed enhanced proteinase K resistance and increased detergent insolubility. The close similarities displayed by both mutations point to a common pathological mechanism that differs from other prion diseases, thus arguing for a distinct class of disease.'