Cystatin F is a biomarker of prion pathogenesis in mice.
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.
Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
Mario
M
Nuvolone
Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
Nicolas
N
Schmid
Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
Gino
G
Miele
Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
Silvia
S
Sorce
Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
Rita
R
Moos
Cytos Biotechnology AG, Zurich-Schlieren, Switzerland.
Christian
C
Schori
Cytos Biotechnology AG, Zurich-Schlieren, Switzerland.
Roger R
RR
Beerli
Cytos Biotechnology AG, Zurich-Schlieren, Switzerland.
Monika
M
Bauer
Cytos Biotechnology AG, Zurich-Schlieren, Switzerland.
Philippe
P
Saudan
Cytos Biotechnology AG, Zurich-Schlieren, Switzerland.
Klaus
K
Dietmeier
AJ Roboscreen GmbH, Leipzig, Germany.
Ingolf
I
Lachmann
Department of Neurology, University Hospital Zurich, Zurich, Switzerland.
Michael
M
Linnebank
Department of Neurology, University Hospital Zurich, Zurich, Switzerland.
Roland
R
Martin
Department of Neurology, University Hospital Zurich, Zurich, Switzerland.|Department of Neurology; Bern University Hospital and University of Bern, Bern, Switzerland.
Ulf
U
Kallweit
Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
Veronika
V
Kana
Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
Elisabeth J
EJ
Rushing
Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
Herbert
H
Budka
Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
Adriano
http://orcid.org/0000-0002-0344-6708
A
Aguzzi
D000818:Animals; D015415:Biomarkers; D001921:Brain / Q000378:metabolism / Q000473:pathology; D015891:Cystatins / Q000134:cerebrospinal fluid / Q000235:genetics / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D017096:Prion Diseases / Q000134:cerebrospinal fluid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D015415:Biomarkers; D015891:Cystatins; D012333:RNA, Messenger; C550521:cystatin F, mouse