BAMBI and CHGA in Prion Diseases: Neuropathological Assessment and Potential Role as Disease Biomarkers.

Óscar López-Pérez,Janne Markus Toivonen,Marina Betancor,Rosa Bolea,Alicia Otero,Adelaida Hernaiz,Marcos Bernal-Martín,Juan José Badiola,Inga Zerr,Pilar Zaragoza,Franc Llorens,Inmaculada Martín-Burriel

doi:10.3390/biom10050706

Abstract

Prion diseases affect both animals and humans. Research in the natural animal model of the disease could help in the understanding of neuropathological mechanisms and in the development of biomarkers for human pathologies. For this purpose, we studied the expression of 10 genes involved in prion propagation in vitro in the central nervous system of scrapie-infected sheep. Dysregulated genes (BAMBI and CHGA) were further analysed in a transgenic murine model (Tg338) of scrapie, and their protein distribution was determined using immunohistochemistry and Western blot. Their potential as biomarkers was finally assessed using enzyme-linked immunosorbent assay (ELISA) in cerebrospinal fluid (CSF) of scrapie sheep and Creutzfeldt-Jakob disease (CJD) patients. Protein BAMBI was upregulated in highly affected brain areas and CHGA was overexpressed along the brain in both models. Moreover, BAMBI and CHGA immunostaining scores strongly correlated with spongiosis and microgliosis in mice. Finally, levels of BAMBI were significantly higher in the CSF of clinical sheep and CJD patients. In addition to their potential as biomarkers, our work confirms the role of BAMBI and CHGA in prion neuropathology in vivo, but besides prion replication, they seem to be involved in the characteristic neuroinflammatory response associated to prion infection.

Highlights

Transmissible spongiform encephalopathies (TSE), or prion diseases, are fatal neurodegenerative disorders caused by prions [1]
Two-way analysis of variance (ANOVA) revealed a significant effect of the disease in the expression profile of the ten genes, which explained 17% of variation (p = 0.02), and the Bonferroni post-test confirmed the effect of scrapie in the upregulation of BAMBI (p < 0.05)
Due to the difficulty of finding controls with the same genotype, animals used as controls were obtained from culling sheep from a scrapie-free flock, which were of the same sex and breed, but significantly older than the scrapie-affected animals (Table S1)

Summary

Introduction

Transmissible spongiform encephalopathies (TSE), or prion diseases, are fatal neurodegenerative disorders caused by prions [1] These pathologies affect humans and animals and share common pathological features such as accumulation of abnormal conformers (PrPSc) of the cellular prion protein (PrPc) in the central nervous system (CNS), which leads to neuronal dysfunction and cell death. Transcriptomic studies have revealed differentially expressed genes that could be involved in the pathogenesis of prion diseases and are potential targets for therapies in humans [3,4,5]. Most of these studies were done using mice infected with different prion strains [4]. Similarities observed between ovine scrapie and human neurodegenerative diseases support research in the natural animal model of the disease for the development of biomarkers for diagnosis and therapy and for the study of the molecular mechanisms of prion neuropathology [6,7,8]

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