Fatal familial insomnia and familial Creutzfeldt-Jakob disease: different prion proteins determined by a DNA polymorphism.

Abstract

Fatal familial insomnia and a subtype of Creutzfeldt-Jakob disease, two clinicaly and pathologically distinct dies, are linked to the same mutation at codon 178 (Asp-178 --Asn) but segregate with different genotypes de-termined by this mutation and the methionivaline polymorphism at codon 129 of the prion protein gene. The abnormal isoforms of the prion protein in these two diseases were found to differ both in the relative abundance of glycosylated forms and in the size of the protease-restant fagments. The size difference was consistent with a different protease cleavage site, suggesting a different conformation of the protease-resistant prion protein present in the two diseases. These differences are likely to be responsible for the type and location of the lesions that characterize these two diseases. Therefore, the combination of the mutation at codon 178 and the polymorphism at codon 129 determines the disease phenotype by producing two altered conformations of the prion protein.Prion diseases, also called spongiform encephalopathies or transmissible amyloidoses, are a group of sporadic, iatrogenic, and familial diseases that affect humans and animals (1-3). The human familial forms include three major groups: (i) Creutzfeldt-Jakob disease (CJD), a subacute dementing illness usually associated with cerebellar signs, myoclonus, and spongiform degeneration (4, 6); (ii) GertsmannStraussler-Scheinker syndrome (GSS), a chronic condition characterized by ataxia, dementia, and the presence of amyloid plaques (4-6); and (iii) fatal familial insomnia (FFI), characterized by a loss of the ability to sleep, dysautonomia, selective atrophy of the thalamus, and usually no spongiform changes (7-11). Within these three groups there are subtypes defined by specific mutations in the prion protein (PrP) gene (PRNP). Mutations at PRNP codons 102, 105, 117, 198, and 217 are associated with GSS subtypes (12,13), while a mutation at codon 200 is linked to one CJD subtype, CJD2m (14). A mutation at codon 178 that results in the replacement of aspartic acid by asparagine (Asp-178 --Asn) is shared by FFI and another CJD subtype, CJD178 (4,(15)(16)(17). In spite of the common mutation, these two diseases are phenotypically distinct since in CJD178 severe sleep impairment has not been reported and there is widespread spongiosis rather than selective thalamic atrophy. Also, in contrast to FFI, CJD178 has been consistently transmitted to receptive animals (18).We recently showed that FFI and CJD178 segregate with distinct PRNP genotypes determined by a common methionine-valine polymorphism at codon 129 of the mutant allele that specifies methionine in FFI and valine in CJD178 (18).

A refined method for molecular typing reveals that co-occurrence of PrPSc types in Creutzfeldt–Jakob disease is not the rule

“…17,19,29,44 Yull et al 35 found that the type 1-like band detected by 12B2 in vCJD maintained the very characteristic glycoform ratio of PrP Sc type 2B and concluded that the band they considered a PrP Sc resistant core could not be a common type 1. We consider this result, which was also reproduced by us, as further evidence that the type 1-like band recognized by 12B2 in vCJD cases represents partially cleaved fragments of PrP Sc type 2B rather than real, bona fide PrP Sc type 1.…”

“…Although uncertainties remain on the molecular basis of TSE strains and the relationship between strains and PrP, several lines of evidence indicate that PrP Sc exists in a variety of molecular subtypes showing distinctive physicochemical properties 13,[17][18][19][20][21][22][23][24][25] (for reviews about more recent studies see Parchi et al 26 and Baron et al 27 ). Most significantly, PrP Sc molecules derived from different strains or disease variants with distinct pathology often vary in their N-terminal site of PK cleavage.…”

Involvement of Dab1 in APP processing and β-amyloid deposition in sporadic Creutzfeldt–Jakob patients

“…Although sCJD is rare, with an incidence of 0.6-1.2 per million, it accounts for about 85% of all recognized human cases of prion disease (Brandel et al, 2000;Hill et al, 2003). Two predominant PrP sc types have been identified, based on the gel mobility of the PrP sc fragments resistant to proteinase K (PK) treatment, and they are associated with different CJD phenotypes (Cali et al, 2006;Gambetti et al, 2003;Monari et al, 1994;Petersen et al, 1994). Parallel to this, PRNP polymorphism at codon 129 (Met 129 →Val) modulates sensitivity to CJD, and methionine homozygosis is a risk factor for sporadic and variant CJD (Collinge, 1999;Ladogana et al, 2005;Palmer et al, 1991).…”

Molecular characterization of proteolytic cleavage sites of the Pseudomonas syringae effector AvrRpt2

“…Persuasive evidence that strain-specific information is enciphered in the tertiary structure of PrP Sc comes from transmission of two different inherited human prion diseases to mice expressing a chimeric MHu2M PrP transgene (27). In FFI, the protease-resistant fragment of PrP Sc after deglycosylation has a mass of 19 kDa, whereas in fCJD(E200K) and most sporadic prion diseases it is 21 kDa (Table 6) (273,274). This difference in molecular size was shown to be due to different sites of proteolytic cleavage at the NH 2 termini of the two human PrP Sc molecules reflecting different tertiary structures (273).…”