This latter is less soluble in detergent and is partially resistant to PK digestion. The D178N mutation reduces the structural stability of the PrP C, which is more prone to convert into PrP Sc and aggregate ( Liemann and Glockshuber, 1999). All PrP C species are soluble in detergent and sensitive to proteinase K (PK) digestion. The pattern of glycosylation gives rise to different PrP C forms: the di-glycosylated (70%), the mono-glycosylated (25%), and the un-glycosylated (5%) species ( Caughey et al., 1989 Rudd et al., 1999). Finally, in the Golgi apparatus, the oligosaccharides are modified to produce complex-type chains rich in sialic acid ( Caughey et al., 1989), which have an important role in targeting PrP C to neuronal synapses ( Bate et al., 2016). PrP C is synthesized in the rough endoplasmic reticulum where it undergoes several post-translation modifications, including the addition of a GPI anchor to its C-terminal part, the formation of a disulfide bridge between two cysteine residues (Cys179-Cys214), and the N-linked glycosylation at two asparagine residues (Asn181 and Asn197) ( Turk et al., 1988). Several lines of evidence suggest that codon 129 polymorphism in PRNP does not influence the age at disease onset ( Montagna et al., 2006). ![]() The presence of MV (FFI D178N-129MV) is associated with longer disease duration (20–35 months) with equilibrium and gait dysfunctions, while the presence of VV causes a distinct genetic disease, referred to as familial Creutzfeldt–Jakob disease (fCJD D178N-129VV) ( Gambetti et al., 1995). For instance, the presence of MM (FFI D178N-129MM) causes FFI with rapid progression (7–18 months), sleep disturbances, and dysautonomia. The polymorphism at codon 129 of the PRNP (methionine or valine ) plays a significant role in disease heterogeneity ( Monari et al., 1994). In cases of long disease duration, such alterations involve also the cerebral cortex. The pathology primarily affects the thalamus that shows neuronal loss, spongiform changes, astrogliosis, and moderate PrP Sc deposition ( Montagna et al., 2003 Macchi et al., 1997). Since a main clinical feature of the disease was the presence of a severe and untreatable insomnia, it was named FFI. In 1992, it was shown that the cause of the disease is an autosomal-dominant mutation at codon 178 of the PrP C encoding gene ( PRNP), resulting in aspartic acid (D) to asparagine (N) substitution (D178N) ( Medori et al., 1992). ![]() Fatal Familial Insomnia (FFI) is a genetic prion disorder caused by the conformational conversion of the cellular form of the prion protein (PrP C) into an abnormally folded conformer, named prion or PrP Sc, which acquires toxic properties and accumulates in the brain ( Lugaresi et al., 1986).
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