Abstract
The normal cellular isoform of prion protein, designated PrPC, is constitutively converted to the abnormally folded, amyloidogenic isoform, PrPSc, in prion diseases, which include Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy in animals. PrPC is a membrane glycoprotein consisting of the non-structural N-terminal domain and the globular C-terminal domain. During conversion of PrPC to PrPSc, its 2/3 C-terminal region undergoes marked structural changes, forming a protease-resistant structure. In contrast, the N-terminal region remains protease-sensitive in PrPSc. Reverse genetic studies using reconstituted PrPC-knockout mice with various mutant PrP molecules have revealed that the N-terminal domain has an important role in the normal function of PrPC and the conversion of PrPC to PrPSc. The N-terminal domain includes various characteristic regions, such as the positively charged residue-rich polybasic region, the octapeptide repeat (OR) region consisting of five repeats of an octapeptide sequence, and the post-OR region with another positively charged residue-rich polybasic region followed by a stretch of hydrophobic residues. We discuss the normal functions of PrPC, the conversion of PrPC to PrPSc, and the neurotoxicity of PrPSc by focusing on the roles of the N-terminal regions in these topics.
Highlights
Conformational conversion of the normal cellular isoform of prion protein, designated PrPC, to the abnormally folded, amyloidogenic isoform, PrPSc, is a key pathogenic event in prion diseases, a group of fatal neurodegenerative disorders that include Creutzfeldt–Jakob disease (CJD) in humans, scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, and chronic wasting disease in deer [1,2,3,4].These diseases are pathologically characterized by neuronal cell loss, spongiform degeneration, gliosis, and PrPSc accumulation in the brain [5]
We have shown that Tg(PrP∆25–50)/Prnp0/0 mice developed disease without elongated incubation times after infection with RML and 22L prions (Table 1) [64], suggesting that the remaining residues 23 and 24 in PrP∆25–50 could be enough for the polybasic region to support prion pathogenesis
We showed that Prnp0/0 mice transgenic for mouse PrP with substitutions of lysine residues at positions 23, 24, and 27 to alanine residues, or PrP3K3A, markedly reduced their susceptibility to RML and 22L scrapie prions (Table 1) [66], suggesting that positively charged residues in residues 23–24 and 27–31 could be important for the polybasic region to support prion pathogenesis
Summary
Conformational conversion of the normal cellular isoform of prion protein, designated PrPC, to the abnormally folded, amyloidogenic isoform, PrPSc, is a key pathogenic event in prion diseases, a group of fatal neurodegenerative disorders that include Creutzfeldt–Jakob disease (CJD) in humans, scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, and chronic wasting disease in deer [1,2,3,4]. These diseases are pathologically characterized by neuronal cell loss, spongiform degeneration, gliosis, and PrPSc accumulation in the brain [5]. SS, signal peptide; OR: octapeptide repeats; HR, hydrophobic region; GPI, GPI anchor signal sequence; α, α-helix; β, β-sheet
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