Cellular Phenotyping of Secretory and Nuclear Prion Proteins
Associated with Inherited Prion Diseases*
Holger
Lorenz,
Otto
Windl, and
Hans A.
Kretzschmar
From the Institut für Neuropathologie,
Ludwig-Maximilians-Universität München,
D-81377 München, Germany
The pathogenic mechanisms leading from mutations
in the prion protein (PrP) gene to infectious disease are not
understood. To investigate the possibility that cellular processing of
mutant prion protein may contribute to the formation of infectious
particles, a mouse PrP model system has been established using the
green fluorescent protein. Three novel PrP mutants were examined
employing this model system and compared with wild type as well as
known mutant PrPs. Two Creutzfeldt-Jakob disease-associated PrP
mutants, PrP T188K and PrP T188R, revealed a secretory pathway to the
cell membrane and PrPSc-like properties,
i.e. enhanced proteinase K resistance and detergent insolubility similar to other mutant PrPs associated with familial prion diseases. Moreover, a recently described disease-related truncated PrP mutant, PrP Q160Stop, showed an almost
exclusive localization in the nucleus and a catabolism along the
proteasomal pathway. Therefore, various distinct pathological
mechanisms may cause prion diseases, and aberrant cellular processing
may be included in the pathogenesis of prion diseases.
*
This work was supported by European Commission Grant
BMH4-97-2679 and by the Deutsche Forschungsgemeinschaft
(Sonderforschungsbereich Grant 596).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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