Abstract
Misfolding of the cellular prion protein (PrPC) into the scrapie prion protein (PrPSc) results in progressive, fatal, transmissible neurodegenerative conditions termed prion diseases. Experimental and epidemiological evidence point toward a protracted, clinically silent phase in prion diseases, yet there is no diagnostic test capable of identifying asymptomatic individuals incubating prions. In an effort to identify early biomarkers of prion diseases, we have compared global transcriptional profiles in brains from pre-symptomatic prion-infected mice and controls. We identified Cst7, which encodes cystatin F, as the most strongly upregulated transcript in this model. Early and robust upregulation of Cst7 mRNA levels and of its cognate protein was validated in additional mouse models of prion disease. Surprisingly, we found no significant increase in cystatin F levels in both cerebrospinal fluid or brain parenchyma of patients with Creutzfeldt-Jakob disease compared to Alzheimer’s disease or non-demented controls. Our results validate cystatin F as a useful biomarker of early pathogenesis in experimental models of prion disease, and point to unexpected species-specific differences in the transcriptional responses to prion infections.
Highlights
Prion diseases or transmissible spongiform encephalopathies are rare, late-onset, rapidly progressing and fatal infectious neurodegenerative disorders [1]
We focused on frontal cortex, a brain area commonly affected both by amyloid β pathology in Alzheimer’s disease and by partially PKresistant prion protein (PrP) in Creutzfeldt-Jakob disease, as well as on cerebellum, which is rarely involved by amyloid β pathology in Alzheimer’s disease [7,36,37]
Microglial Cst7 can be induced by lipopolysaccharide challenge, and moderately increased Cst7 levels were observed in different mouse models of neurodegenerative and neuroinflammatory conditions with microgliosis
Summary
Prion diseases or transmissible spongiform encephalopathies are rare, late-onset, rapidly progressing and fatal infectious neurodegenerative disorders [1]. They include sporadic, genetic, variant or iatrogenic Creutzfeldt-Jakob disease (CJD) in humans, ovine scrapie, bovine spongiform encephalopathy, and chronic wasting disease of deer and elk [1]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Cytos Biotechnology and AJ Roboscreen GmbH provided support in the form of salaries for authors CS, RRB, MB, PS and KD (Cytos Biotechnology AG) and IL (AJ Roboscreen GmbH), but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
