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J. Biol. Chem., Vol. 276, Issue 14, 11265-11271, April 6, 2001
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From the The central event in prion disease is thought to
be conformational conversion of the cellular isoform of prion protein
(PrPC) to the insoluble isoform PrPSc. We
generated polyclonal and monoclonal antibodies by immunizing PrPC-null mice with native PrPC. All seven
monoclonal antibodies (mAbs) immunoprecipitated PrPC, but
they immunoprecipitated PrPSc weakly or not at all, thereby
indicating preferential reactivities to PrPC in solution.
Immunoprecipitation using these mAbs revealed a marked loss of
PrPC in brains at the terminal stage of illness. Histoblot
analyses using these polyclonal antibodies in combination of
pretreatment of blots dissociated PrPC and
PrPSc in situ and consistently demonstrated the
decrease of PrPC at regions where PrPSc
accumulated. Interestingly, same mAbs showed immunohistochemical reactivities to abnormal isoforms. One group of mAbs showed reactivity to materials that accumulated in astrocytes, while the other group did
so to amorphous plaques in neuropil. Epitope mapping indicated that
single mAbs have reactivities to multiple epitopes, thus implying dual
specificities. This suggests the importance of octarepeats as a part of
PrPC-specific conformation. Our observations support the
notion that loss of function of PrPC may partly underlie
the pathogenesis of prion diseases. The conversion of PrPC
to PrPSc may involve multiple steps at different sites.
In Vivo Conversion of Cellular Prion
Protein to Pathogenic Isoforms, as Monitored by Conformation-specific
Antibodies*
,,§,,,
,, and National Institute of Animal Health,
Tsukuba, Ibaraki 305-0856, Japan, § Nippi Research Institute
of Biomatrix, Adachi, Tokyo 120-8601, Japan, ¶ Brain Science
Institute, RIKEN, Wako, Saitama 351-0198, Japan, and Institute
for Virus Research, Kyoto University, Sakyo-ku,
Kyoto 606-8507, Japan
*
This work was supported by grants from the Science and
Technology Agency of Japan, and the Ministry of Agriculture, Forestry, and Fisheries, Japan.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.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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