Abstract
Conformational conversion of the cellular prion protein, PrPC, into the abnormally folded isoform, PrPSc, is a key pathogenic event in prion diseases. However, the exact conversion mechanism remains largely unknown. Transgenic mice expressing PrP with a deletion of the central residues 91–106 were generated in the absence of endogenous PrPC, designated Tg(PrP∆91–106)/Prnp0/0 mice and intracerebrally inoculated with various prions. Tg(PrP∆91–106)/Prnp0/0 mice were resistant to RML, 22L and FK-1 prions, neither producing PrPSc∆91–106 or prions in the brain nor developing disease after inoculation. However, they remained marginally susceptible to bovine spongiform encephalopathy (BSE) prions, developing disease after elongated incubation times and accumulating PrPSc∆91–106 and prions in the brain after inoculation with BSE prions. Recombinant PrP∆91-104 converted into PrPSc∆91–104 after incubation with BSE-PrPSc-prions but not with RML- and 22L–PrPSc-prions, in a protein misfolding cyclic amplification assay. However, digitonin and heparin stimulated the conversion of PrP∆91–104 into PrPSc∆91–104 even after incubation with RML- and 22L-PrPSc-prions. These results suggest that residues 91–106 or 91–104 of PrPC are crucially involved in prion pathogenesis in a strain-dependent manner and may play a similar role to digitonin and heparin in the conversion of PrPC into PrPSc.
Highlights
The normal cellular isoform of prion protein, designated PrPC, is a glycoprotein tethered to the outer cell membrane via a glycosylphosphatidylinositol (GPI) anchor moiety and expressed most abundantly in the brain, by neurons [1,2]
Its conformational conversion into the abnormally folded amyloidogenic isoform, PrPSc, which is believed to be a major component of infectious prions, is a key pathogenic event in prion diseases, a group of neurodegenerative disorders, including Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy (BSE) in animals [1,2]
These results suggest that residues 91–106, which are completely deleted in PrP∆32–106 and partially in PrP∆32–93 but intact in PrP∆32–80 and PrP∆octapeptide repeat (OR), could play a role in the conversion of PrPC into PrPSc and prion pathogenesis after prion infection
Summary
The normal cellular isoform of prion protein, designated PrPC, is a glycoprotein tethered to the outer cell membrane via a glycosylphosphatidylinositol (GPI) anchor moiety and expressed most abundantly in the brain, by neurons [1,2]. 51–90, which correspond to the so-called octapeptide repeat (OR) region, were susceptible to RML and 22L scrapie prions, developing disease without an elongated incubation time and accumulating PrPSc∆OR in the brain [9,10] These results indicate that, in contrast to residues 23–31, residues from position 32 to 90 may be dispensable for the conversion of PrPC into PrPSc, as well as to support prion infection. PrP with a deletion further extended to position 106 or PrP∆32–106, failed to convert into PrPSc or support prion pathogenesis in Prnp0/0 mice after intracerebral inoculation with RML prions [12] These results suggest that residues 91–106, which are completely deleted in PrP∆32–106 and partially in PrP∆32–93 but intact in PrP∆32–80 and PrP∆OR, could play a role in the conversion of PrPC into PrPSc and prion pathogenesis after prion infection. These results suggest that residues 91–106 or 91–104 of PrPC are crucial for prion pathogenesis in a strain-dependent manner and may play a similar role to digitonin and heparin in the conversion of PrPC into PrPSc
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