Two distinct prions in fatal familial insomnia and its sporadic form

Abstract

Fatal familial insomnia is a genetic prion disease, which is associated with the aspartic acid to asparagine substitution at codon 178 of the prion protein gene. Although the hallmark pathological feature is thalamic and olivary degeneration, there is a patient with an atypical fatal familial insomnia without the hallmark feature. The cause of the pathological variability is unclear. We analysed a Japanese fatal familial insomnia kindred and compared one atypical clinicopathological fatal familial insomnia phenotype case and typical fatal familial insomnia phenotype cases with transmission studies using multiple lines of knock-in mice and with protein misfolding cyclic amplification. We also analysed the transmissibility and the amplification properties of sporadic fatal insomnia. Transmission studies revealed that the typical fatal familial insomnia with thalamic and olivary degeneration showed successful transmission only using knock-in mice expressing human–mouse chimeric prion protein gene. The atypical fatal familial insomnia with spongiform changes showed successful transmission only using knock-in mice expressing bank vole prion protein gene. Two sporadic fatal insomnia cases with thalamic and olivary degeneration showed the same transmissibility as the typical fatal familial insomnia phenotype. Interestingly, one sporadic fatal insomnia case with thalamic/olivary degeneration and spongiform changes showed transmissibility of both the typical and atypical fatal familial insomnia phenotypes. Protein misfolding cyclic amplification could amplify both typical fatal familial insomnia cases and sporadic fatal insomnia cases but not the atypical fatal familial insomnia phenotype or other sporadic Creutzfeldt–Jakob disease subtypes. In addition to clinical findings and neuropathological features, the transmission properties and the amplification properties were different between the typical and atypical fatal familial insomnia phenotypes. It is suggested that two distinct prions were associated with the diversity in the fatal familial insomnia phenotype, and these two prions could also be detected in sporadic fatal insomnia.

PMCA-generated prions from the olfactory mucosa of patients with Fatal Familial Insomnia cause prion disease in mice

“…BvPrP with methionine at codon 109 of Prnp (22). Our work confirmed that also our model is susceptible to FFI.…”

“…This has been observed also in transgenic mice expressing BvPrP with isoleucine at codon 109 and the D178 mutation that spontaneously developed prion diseases with the presence of a PrP res with a predominant di-glycosylated band (34). Many other studies showed that this phenomenon occurred also in other transgenic mouse models inoculated with FFI thus suggesting that, regardless of the recipient mice, some biochemical features typical of the FFI are reproduced after inoculation (21,22).…”

“…There is a compelling evidence that some human prion strains originally believed to be "pure" are instead composed by a mixture of strains (35)(36)(37)(38). Interestingly, a very recent publication of the group of Kitamoto Tetsuyuki showed that even the FFI D178N-129MM strain might not be pure and that at least two distinct prion strains can be responsible for the disease, one associated with the typical clinical presentation of the disease and the other associated with an atypical phenotype (22). It is therefore conceivable that the mono-glycosylated PrP res observed in one of the animals inoculated with FFI-BH might have emerged either because the FFI propagates as a mixture of prions (as also shown for other sporadic forms of prion diseases) or as a random event due to specific limitations imposed by the animal model used.…”

“…The ability of the D178N mutation to promote conversion of PrP C into PrP Sc which results in the generation of spontaneous prion pathology was shown in mice genetically modified to express murine PrP with the D177N mutation (the equivalent to human D178N) where PrP Sc is barely detectable (13,14). The infectious properties of FFI-PrP Sc were extensively investigated by transmission studies in wild-type animals (15,16) and in several lines of mice genetically modified to express human PrP (17,18) as well as primates (15,(19)(20)(21)(22). Results of these studies showed that several factors, including the polymorphisms at codon 129 of the incoming FFI-PrP Sc inoculum, the prion titer of the FFI brain areas used to challenge the animals and the PrP C amino acid sequence of the recipient animals, could significantly influence the transmission efficiency.…”

“…Notably, when inoculated in mice expressing a chimeric human-mouse PrP, FFI-PrP Sc is able to promote the generation of prions characterized by similar biochemical features of the original inoculum (21). In a recent report, FFI was efficiently transmitted to knock-in mice expressing the bank vole PrP (BvPrP) with methionine at codon 109 of the PrP C (22). Also in this case, the PrP Sc generated in mice showed the typical biochemical features of FFI-PrP Sc (predominance of the diglycosylated band and migration of the un-glycosylated PrP species at 19kDa).…”