Abstract
Scrapie is a neurodegenerative disorder belonging to the group of transmissible spongiform encephalopathy (TSE). Scrapie occurs in sheep and goats, which are considered good natural animal models of these TSE. Changes in DNA methylation occur in the central nervous system (CNS) of patients suffering from prion-like neurodegenerative diseases, such as Alzheimer's disease. Nevertheless, potential DNA methylation alterations have not yet been investigated in the CNS of any prion disease model or naturally infected cases, neither in humans nor in animals. Genome-wide DNA methylation patterns were studied in the thalamus obtained from sheep naturally infected with scrapie at a clinical stage (n = 4) and from controls (n = 4) by performing a whole-genome bisulfite sequencing (WGBS) analysis. Ewes carried the scrapie-susceptible ARQ/ARQ PRNP genotype and were sacrificed at a similar age (4–6 years). Although the average genomic methylation levels were similar between the control and the scrapie animals, we identified 8,907 significant differentially methylated regions (DMRs) and 39 promoters (DMPs). Gene Ontology analysis revealed that hypomethylated DMRs were enriched in genes involved in transmembrane transport and cell adhesion, whereas hypermethylated DMRs were related to intracellular signal transduction genes. Moreover, genes highly expressed in specific types of CNS cells and those previously described to be differentially expressed in scrapie brains contained DMRs. Finally, a quantitative PCR (qPCR) validation indicated differences in the expression of five genes (PCDH19, SNCG, WDR45B, PEX1, and CABIN1) that matched the methylation changes observed in the genomic study. Altogether, these results suggest a potential regulatory role of DNA methylation in prion neuropathology.
Highlights
Prion diseases are fatal and transmissible neurodegenerative disorders that occur in humans and animals [1]
To the best of our knowledge, and in contrast to Alzheimer’s disease (AD) [38], Parkinson’s disease (PD) [41], and amyotrophic lateral sclerosis (ALS) [42], only one study has analyzed the genome-wide methylation profile in prion diseases, and this was performed in peripheral blood of sporadic Creutzfeldt–Jakob disease (sCJD) patients [23]
We report here the first wholegenome bisulfite sequencing (WGBS) study carried out in the central nervous system (CNS) of any prion disease model
Summary
Prion diseases are fatal and transmissible neurodegenerative disorders that occur in humans and animals [1] These diseases are caused by the conformational conversion of the cellular prion protein (PrPC) to an infectious isoform PrPSc, which is partially resistant to proteases and prone to form aggregates [2]. Several transcriptomic studies performed in sheep have reported differentially expressed genes (DEGs) and proteins that seem to be involved in the pathogenesis of scrapie and other neurodegenerative diseases including human prion diseases [5–8]. These common findings between scrapie and human prion diseases support the use of scrapie sheep as a good natural animal model to study the molecular mechanisms of prion neuropathology and to identify potential diagnostic and therapeutic biomarkers for prion diseases
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