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  • These PrPIF are detected in untreated brain extracts


    These PrPIF are detected in untreated n-acetyl-l-cysteine extracts but are consistently enriched following proteinase K (PK) treatment. The biochemical characterization of pathologic PrP has been carried out in most hereditary PrP cerebral amyloidosis associated with PrP mutations and the biochemical PrP patterns correlate with the clinical and pathologic phenotypes. We describe biochemical PrP patterns associated with each mutation and, for simplicity, we represent only the resulting monomers.
    Dominantly inherited prion protein cerebral amyloidoses
    Dominantly inherited prion protein cerebral amyloidoses
    Dominantly inherited prion protein cerebral amyloidoses: variable phenotypes
    Differential diagnosis of dominantly inherited prion protein cerebral amyloidoses Conventional MRI examination is not diagnostic since the lesion patterns observed in dominantly inherited PrP cerebral amyloidoses are comparable to those seen in other neurodegenerative disorders, such as, for example, a marked atrophy of the cerebral cortex, cerebellar vermis, and hemispheres, and of the brainstem. P105S-129V mutation should be considered in the presence of a hyperintense signal of the caudate and putamen, and of the cerebral cortex in DWI. In addition, MRI in patients with the P102L mutation might show a widespread cerebral cortical hyperintensity, involving caudate nuclei in DWI, as also observed in sporadic CJD, or more rarely, an involvement of bilateral pulvinar, as in variant CJD (Kanata et al., 2008). Cerebrospinal fluid surrogate biomarkers, such as 14.3.3 or tau protein levels, are helpful in determining the rate of disease progression, but are not diagnostic. Among the most reliable diagnostic tools developed in recent years for prion diseases is the real-time quaking-induced conversion (RT-QuIC) assay. This assay has n-acetyl-l-cysteine been highly effective in detecting prion-seeding activity in cerebrospinal fluid and olfactory epithelium of patients with sporadic and genetic CJD. In GSS mutations, CSF had been tested in P102L mutation, showing a positive result in 90% of patients (Sano et al., 2013) and in 50% of olfactory mucosa (OM) samples (Bongianni et al., 2017). RT-QuIC was positive in the cerebrospinal fluid of a single case of D202N mutation and in another with an insertion of eight repeats and negative in a A117V case (Franceschini et al., 2017). However, the number of samples tested is too low to draw any conclusions about test sensitivity. RT-QuIC has been shown to efficiently amplify brain homogenate from A117V, F198S, and H187R mutations by using PrP bank vole as amplification substrate, but no data are available from cerebrospinal fluid or other biologic fluids in patients (OrrĂ¹ et al., 2015). For a neuropathologic diagnosis, PrP immunohistochemistry is essential to separate GSS from other nonprion diseases associated with amyloid deposition in the central nervous system. A differential diagnosis between GSS associated with the P102L-129M haplotype and some forms of CJD, including variant CJD, may be difficult if carried out only using PrP immunohistochemistry. As mentioned above, Western blot analysis is essential to differentiate the biochemical pattern of PrPres associated with GSS mutations from the various forms of CJD. When a dominantly inherited PrP cerebral amyloidosis is clinically suspected, molecular genetic analyses are the final step.
    Pathogenesis of the dominantly inherited prion protein cerebral amyloidoses The pathogenesis of dominantly inherited PrP cerebral amyloidoses remains largely unknown and, in particular, a unique feature is that distinct mutations in PRNP cause PrP to acquire an abnormal conformation, resulting in the formation of protease-resistant amino- and carboxy-terminal-truncated PrP peptides that have high fibrillogenic properties. These truncated peptides are mainly composed of mutated PrP, and accumulate extracellularly, leading to the formation of amyloid deposits in brain tissue and/or vessel walls. In vitro studies have shown that synthetic peptides corresponding to the PrP fragments extracted from brain tissue are readily assembled into amyloid fibrils (Tagliavini et al., 1993).