The cellular prion protein and its derived fragments in human prion diseases and their role as potential biomarkers.

Introduction: Human prion diseases are a heterogeneous group of incurable and debilitating conditions characterized by a progressive degeneration of the central nervous system. The conformational changes of the cellular prion protein and its formation into an abnormal isoform, spongiform degeneration, neuronal loss, and neuroinflammation are central to prion disease pathogenesis. It has been postulated that truncated variants of aggregation-prone proteins are implicated in neurodegenerative mechanisms. An increasing body of evidence indicates that proteolytic fragments and truncated variants of the prion protein are formed and accumulated in the brain of prion disease patients. These prion protein variants provide a high degree of relevance to disease pathology and diagnosis. Areas covered: In the present review, we summarize the current knowledge on the occurrence of truncated prion protein species and their potential roles in pathophysiological states during prion diseases progression. In addition, we discuss their usability as a diagnostic biomarker in prion diseases. Expert opinion: Either as a primary factor in the formation of prion diseases or as a consequence from neuropathological affection, abnormal prion protein variants and fragments may provide independent information about mechanisms of prion conversion, pathological states, or disease progression.

Association of prion protein genotype and scrapie prion protein type with cellular prion protein charge isoform profiles in cerebrospinal fluid of humans with sporadic or familial prion diseases.

The present study investigates whether posttranslational modifications of cellular prion protein (PrP(C)) in the cerebrospinal fluid (CSF) of humans with prion diseases are associated with methionine (M) and/or valine (V) polymorphism at codon 129 of the prion protein gene (PRNP), scrapie prion protein (PrP(Sc)) type in sporadic Creutzfeldt-Jakob disease (sCJD), or PRNP mutations in familial Creutzfeldt-Jakob disease (fCJD/E200K), and fatal familial insomnia (FFI). We performed comparative 2-dimensional immunoblotting of PrP(C) charge isoforms in CSF samples from cohorts of diseased and control donors. Mean levels of total PrP(C) were significantly lower in the CSF from fCJD patients than from those with sCJD or FFI. Of the 12 most abundant PrP(C) isoforms in the examined CSF, one (IF12) was relatively decreased in (1) sCJD with VV (vs. MM or MV) at PRNP codon 129; (2) in sCJD with PrP(Sc) type 2 (vs. PrP(Sc) type 1); and (3) in FFI versus sCJD or fCJD. Furthermore, truncated PrP(C) species were detected in sCJD and control samples without discernible differences. Finally, serine 43 of PrP(C) in the CSF and brain tissue from CJD patients showed more pronounced phosphorylation than in control donors.

Codon 129 polymorphism and the E200K mutation do not affect the cellular prion protein isoform composition in the cerebrospinal fluid from patients with Creutzfeldt-Jakob disease.

The cellular prion protein (PrP(c)) is a multifunctional, highly conserved and ubiquitously expressed protein. It undergoes a number of modifications during its post-translational processing, resulting in different PrP(c) glycoforms and truncated PrP(c) fragments. Limited data are available in humans on the expression and cleavage of PrP(c). In this study we investigated the PrP(c) isoform composition in the cerebrospinal fluid from patients with different human prion diseases. The first group of patients was affected by sporadic Creutzfeldt-Jakob disease exhibiting different PrP codon 129 genotypes. The second group contained patients with a genetic form of Creutzfeldt-Jakob disease (E200K). The third group consisted of patients with fatal familial insomnia and the last group comprised cases with the Gerstmann-Sträussler-Scheinker syndrome. We examined whether the PrP codon 129 polymorphism in sporadic Creutzfeldt-Jakob disease as well as the type of prion disease in human patients has an impact on the glycosylation and processing of PrP(c). Immunoblotting analyses using different monoclonal PrP(c) antibodies directed against various epitopes of PrP(c) revealed, for all examined groups of patients, a consistent predominance of the glycosylated PrP(c) isoforms as compared with the unglycosylated form. In addition, the antibody SAF70 recognized a variety of PrP(c) fragments with sizes of 21, 18, 13 and 12 kDa. Our findings indicate that the polymorphisms at PrP codon 129, the E200K mutation at codon 200 or the examined types of human transmissible spongiform encephalopathies do not exert a measurable effect on the glycosylation and processing of PrP(c) in human prion diseases.