Cystatin F is a biomarker of prion pathogenesis in mice

Mario Nuvolone; Nicolas Schmid; Gino Miele; Silvia Sorce; Rita Moos; Christian Schori; Roger R Beerli; Monika Bauer; Philippe Saudan; Klaus Dietmeier; Ingolf Lachmann; Michael Linnebank; Roland Martin; Ulf Kallweit; Veronika Kana; Elisabeth J Rushing; Herbert Budka; Adriano Aguzzi

doi:10.1371/journal.pone.0171923

Cystatin F is a biomarker of prion pathogenesis in mice

PLoS One. 2017 Feb 8;12(2):e0171923. doi: 10.1371/journal.pone.0171923. eCollection 2017.

Authors

Mario Nuvolone¹, Nicolas Schmid¹, Gino Miele¹, Silvia Sorce¹, Rita Moos¹, Christian Schori², Roger R Beerli², Monika Bauer², Philippe Saudan², Klaus Dietmeier², Ingolf Lachmann³, Michael Linnebank⁴, Roland Martin⁴, Ulf Kallweit^{4

5}, Veronika Kana¹, Elisabeth J Rushing¹, Herbert Budka¹, Adriano Aguzzi¹

Affiliations

¹ Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
² Cytos Biotechnology AG, Zurich-Schlieren, Switzerland.
³ AJ Roboscreen GmbH, Leipzig, Germany.
⁴ Department of Neurology, University Hospital Zurich, Zurich, Switzerland.
⁵ Department of Neurology; Bern University Hospital and University of Bern, Bern, Switzerland.

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.

MeSH terms

Animals
Biomarkers
Brain / metabolism
Brain / pathology
Cystatins / cerebrospinal fluid
Cystatins / genetics
Cystatins / metabolism*
Enzyme-Linked Immunosorbent Assay
Gene Expression
Gene Expression Profiling
Humans
Immunohistochemistry
Male
Mice
Prion Diseases / cerebrospinal fluid
Prion Diseases / genetics
Prion Diseases / metabolism*
Prion Diseases / pathology
RNA, Messenger / genetics
RNA, Messenger / metabolism

Substances

Biomarkers
Cystatins
RNA, Messenger
cystatin F, mouse

Grants and funding

AA is the recipient of an Advanced Grant of the European Research Council (ERC, No. 250356) and is supported by grants from the European Union (DEMTEST, NEURINOX), the Swiss National Foundation, the Swiss Initiative in Systems Biology, SystemsX.ch (PrionX, SynucleiX), the Novartis Institutes of Biomedical Research, and the Klinische Forschungsschwerpunkte (KFSPs) "small RNAs" and "Human Hemato-Lymphatic Diseases". GM was supported by a grant from the Swiss National Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. CS, RRB, MB, PS and KD were employed by Cytos Biotechnology AG and IL by AJ Roboscreen GmbH. 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.