NR AOYX
AU Schmalzbauer,R.X.; Windl,O.; Kretzschmar,H.A.
TI Analysis of a new pathogenic mutation (G114V) of human prion protein in vivo and in vitro
QU International Conference - Prion diseases: from basic research to intervention concepts - TSE-Forum, 08.10.-10.10.2003, Gasteig, München - Poster session - BR-14
PT Konferenz-Poster
AB
Diagnostical sequence-analysis revealed a new point-mutation (G114V) located in the central region of the human prion protein (PrP). The age of affected patients is strikingly low (20-25 years); the symptoms resemble those observed in patients afflicted with Gerstmann-Sträussler-Scheinker syndrome (GSS). The mutation G114V and the GSS-associated mutation A117V of PrP were investigated in comparative studies due to the similarities of the clinical picture, their close vicinity on the prion protein and misincorporation of the amino-acid valine in both cases.
Murine and human cell models were used to study biosynthesis and processing of mutant PrP.
Both mutations led to a cellular phenotype distinct from wildtype PrP. Characteristical traits were an impaired transport to the cell surface accompanied by strong accumulation within the endoplasmic reticulum and the cytosol. Specific inhibition of proteasomal degradation exhibited an increase in Proteinase K-resistance and detergent-insolubility. Amyloid staining revealed staining properties that differ from PrPsc, the infectious isoform. Cell-free translocation assays showed that G114V caused favoured synthesis of a transmembrane form (CtmPrP), a trait that had already been described for PrP bearing the A117V mutation.
Together, these data suggest that both mutations represent a distinct group within heritable prion diseases characterized by increased synthesis of transmembrane prion proteins as well as lack of transmissibility.
AD R.X. Schmalzbauer, H.A. Kretzschmar, Institut für Neuropathologie der LMU München, Germany; O. Windl, Veterinary Laboratories Agency Weybridge, Great Britain
SP englisch
PO Deutschland