Prion diseases are progressive chronic neurodegenerative disorders associated with the accumulation of the scrapie prion protein PrP<sup>Sc</sup>, a misfolded conformer of the cellular prion protein PrP<sup>C</sup>.
The C-terminally truncated Y145Stop variant of prion protein (PrP23-144), which is associated with heritable PrP cerebral amyloid angiopathy in humans and also capable of triggering a transmissible prion disease in mice, serves as a useful in vitro model for investigating the molecular and structural basis of amyloid strains and cross-seeding specificities.
Prion diseases are fatal neurodegenerative disorders related to the conformational alteration of the prion protein (PrP C) into a pathogenic and protease-resistant isoform (PrPSc).
Mutations in the protein coding region of the human PrP gene (PRNP), which have been proposed to alter the stability of the PrP protein, have been linked to a number of forms of TSE.
PrP(c) is encoded by the prion protein gene, and a common polymorphism at codon 129 of this gene is a determinant of susceptibility to acquired and sporadic prion diseases but not for sporadic AD.
Amino acids that differentiate ovine and deer normal host prion protein (PrP<sup>C</sup>) and associated with structural rigidity of the loop β2-α2 (S173N, N177T) appear to confer resistance to some prion diseases.
Two Creutzfeldt-Jakob disease-associated PrP mutants, PrPT188K and PrPT188R, revealed a secretory pathway to the cell membrane and PrP(Sc)-like properties, i.e. enhanced proteinase K resistance and detergent insolubility similar to other mutant PrPs associated with familial prion diseases.
A variant of prion encephalopathy associated with the novel H187R mutation in the PRNP gene displays distinctive clinical and immunostaining characteristics that further expand the boundaries of human prion disease.
Prion disease or transmissible spongiform encephalopathies are characterized by the presence of the abnormal form of the prion protein (PrP<sup>Sc</sup>).
The delayed onset of CJD has complicated the analysis of inherited forms of the illness and led to the suggestion that mutations in the prion protein (PrP) gene are necessary but not sufficient for prion disease despite genetic linkage; indeed, an environmental factor such as a ubiquitous virus has been proposed as a second necessary factor.
We have compared the immunomorphological spectrum of the deposition of the disease-associated prion protein (PrP(Sc)) in the cerebral and cerebellar cortex of 32 Creutzfeldt-Jakob disease (CJD) patients with the PrP gene (PRNP) E200K mutation to 45 sporadic CJD and 14 other genetic prion disease cases.
Variant Creutzfeldt-Jakob disease (vCJD) is a novel acquired human prion disease resulting from human exposure to the agent causing bovine spongiform encephalopathy (BSE). vCJD differs from all other human prion diseases in that the disease-associated form of the prion protein and infectivity are present in lymphoid tissues throughout the body.
Fatal familial insomnia is a prion disease with a mutation in codon 178 of the PrP gene, but the disease phenotype seems to differ from that of previously described kindreds with the same point mutation.
Our study reveals that formation of the C-terminal globular domain of PrPC has an impact on membrane anchoring and indicates that misfolded secreted forms of the prion protein are linked to inherited prion diseases in humans.
Here we introduce several PRNP gene mutations (such as, PrP-KDEL, PrP-3AV, PrP-A117V, PrP-G114V, PrP-P102L and PrP-E200K) into the cultured cells in order to explore the pathogenic mechanism of familial prion disease.
Compared to ND, t-PrP concentrations were significantly decreased in sCJD, iCJD and in genetic prion diseases associated with the three most common mutations E200K, V210I (associated with genetic CJD) and D178N-129M (associated with fatal familial insomnia).