It has been proposed that

It has been proposed that a PrP pathogenic mechanism is a toxic gain of function secondary to the misfolding of mutated PrP. However, such a mechanism might not apply to all mutant PrP species, since some mutations had little effect on the stability and folding kinetics of PrP (Swietnicki et al., 1998). In P102L, it has been reported that wild-type PrP is also involved in disease propagation, but with a different distribution from that of PrP P102L, explaining the multiple disease phenotypes associated with P102L mutation (Wadsworth et al., 2006). Patients with dominantly inherited PrP cerebral amyloidoses accumulate PrP, forming deposits with and without amyloid properties. The contribution of both types of deposits to the pathogenesis of these complex diseases remains unknown. To address this issue, Chesebro et al. (2010) developed a mouse model in which, in contrast to normal PrP, the expression of the transgene array results in the formation of a PrP species that is not anchored to the outer cell membrane. Transgenic mice, expressing anchorless PrP inoculated with a mouse-adapted TSE agent, developed an amyloid angiopathy in the absence of spongiform degeneration, a pathology that is highly different from that seen in wild-type mice. Therefore, the topology of PrP appears to modulate the kinetics of PrP deposition as well as the neuropathologic phenotype (Chesebro et al., 2010). Two PRNP mutations associated with GSS variants have been modeled in transgenic mice (Hsiao et al., 1990; Manson et al., 1999; Yang et al., 2009). Overexpression of both PrP P102L and PrP A117V resulted in a neurologic disease in mice characterized histopathologically by variable spongiform degeneration of the gdc-0980 and PrP-containing amyloid plaques (Hsiao et al., 1990; Yang et al., 2009). In contrast, mice expressing wild-type levels of PrP P102L expressed in “knockin” transgenic mouse model remained disease-free during their normal lifespan (Manson et al., 1999). The data suggest that expression of mutant PrP might not always be associated with infectivity. To further address this issue, bioassays using brain extracts from two patients with phenotypically different forms of GSS P102L (one with and one without spongiform degeneration) were inoculated into “knockin” transgenic PrP P102L mice. Efficient transmission of a spongiform encephalopathy was seen only using extracts obtained from the patient with spongiform degeneration. Extracts from a patient without spongiform degeneration led to inefficient transmission of disease and the accumulation of PrP amyloid. In conclusion, these experiments suggest that amyloid formation may be caused by PrP misfolding and aggregation in the absence of an infectious TSE agent (Piccardo et al., 2007). Recently, it has been demonstrated that F198S and A117V mutations associated with an 8-kDa PrPSc fragment were successfully transmitted to bank voles, inducing a prion disease characterized by a spongiform encephalopathy. These findings indicate that the 8-kDa fragment retains infectivity (Pirisinu et al., 2016). A distinct neuropathologic finding in many of the dominantly inherited PrP amyloidoses is the presence of tau pathology. When tau coexists with PrP amyloid deposits, neuronal parykaria and neuronal processes, but not glial cells, appear to contain abnormal tau. Tau is present in neurons as neurofibrillary tangles or as a diffuse tau immunopositivity. The currently available data indicate that, in PrP amyloidosis, 3R/4R tau is present, as in Alzheimer disease. The atomic structure of neurofibrillary tangles has been revealed by cryoelectron microscopy in Alzheimer disease (Fitzpatrick et al., 2017). Similar studies are urgently needed to determine whether in PrP amyloidoses 3R/4R tau is consistently present. The pathogenic role of mutated PrP in inducing tau hyperphosphorylation remains unclear.
Introduction Genetic transmissible spongiform encephalopathies (TSEs) account for approximately 10–15% of human prion diseases worldwide [1], [2]. Historically, three different clinical phenotypes have been identified: Creutzfeldt-Jakob disease (CJD) [3], fatal familial insomnia (FFI) [4], and Gerstmann-Sträussler-Scheinker disease (GSS) [5]. However, since these first descriptions, numerous unusual phenotypes have been reported [6], [7], [8]. In 1985, the PRNP gene was isolated [9], and the first mutations were discovered a few years later [10], [11]. This gene encodes the protein PrP, whose conformational conversion into an abnormal form called PrPsc is responsible for the development of the disease. More than 30 mutations have been identified as being involved in the development of genetic TSE, with a variety of geographical distributions and frequencies [1]. As a result, it now appears necessary to establish correlations between the genetic and clinical features of this disease.