MiRNA expression profiles in the brains of mice infected with scrapie agents 139A, ME7 and S15

Abstract

MicroRNA (miRNA) is a class of non-coding endogenous small-molecule single-stranded RNA that regulates complementary mRNA through degradation or translation of the mRNA targets. Usually, miRNAs show remarkable cell and tissues specificity. Recently, alterations in a set of miRNAs in the brains of patients with certain neurodegenerative diseases, including prion diseases, have been reported. In this study, using deep sequencing technology, miRNA expression profiles in the brains of mice infected with scrapie agents 139A, ME7 and S15 at a terminal stage were comparatively analysed. In total, 57, 94 and 135 differentially expressed miRNAs were identified in the pooled brain samples of 139A-, ME7- and S15-infected mice, respectively, compared with the brains of age-matched normal controls. Among them, 22 were commonly increased and 14 were commonly decreased in the brains of all three infected models. In addition, a reduction in the expression of two novel miRNAs was also commonly observed. Quantitative PCR with reverse transcription analysis of six randomly selected commonly increased and decreased miRNAs in the brains of the three infected mouse models, as well as the two novel miRNAs, verified that the expression patterns were comparable to the deep sequencing data. KEGG analysis of the differentially expressed miRNAs revealed the involvement of similar pathways in all three types of infected animals. Comprehensive analysis of these miRNA profiles not only provides useful clues for understanding prion biology but also is beneficial in the search for possible diagnostic marker(s) for prion diseases.

Regional and subtype-dependent miRNA signatures in sporadic Creutzfeldt-Jakob disease are accompanied by alterations in miRNA silencing machinery and biogenesis

“…A lack of major correlation between regulated miRNAs in sCJD and scrapie-infected mice was detected in high-throughput studies. However, miRNAs: 146a-5p, 342-3p, 142-3p, 26a-5p, 124a-3p (RNA-seq altered and qPCR validated in sCJD) and 338-5p, 18a-3p, 455-5p, 182-5p (RNA-seq altered in sCJD) are commonly altered in at least one of the studies where scrapie miRNA profiles have been investigated [ 21 – 23 , 25 , 33 , 66 ]. Additionally, two miRNAs upregulated in the basis pontis of bovine spongiform encephalopathy-infected macaques, miRNA-342-3p and miRNA-494-3p [ 23 ], were also enriched in sCJD, but exclusively in the FC region.…”

“…In addition, specific miRNA signatures have been proposed for Alzheimer’s (AD), Parkinson’s (PD) and Huntington’s (HD) disease, as well as for Fronto-temporal dementia (FTD) [ 15 – 20 ], supporting the idea that miRNA deregulation is a common hallmark of neurodegenerative diseases. While the study of miRNAs in relation to prion pathogenesis has gained experimental momentum since several miRNAs were found to be altered in in vivo and ex vivo models of prion diseases [ 21 – 25 ], the miRNA signature in sCJD has not been reported so far.…”

MicroRNA Alterations in the Brain and Body Fluids of Humans and Animal Prion Disease Models: Current Status and Perspectives

“…Altered miRNA expression has been investigated in animal and cell culture models including: (a) a sCJD mouse model that recapitulates CJD brain neuropathology ( Padilla et al, 2011 ; Llorens et al, 2014 , 2017 , 2018 ), (b) BSE-infected macaques ( Montag et al, 2009 ) (c) murine models intracerebrally inoculated with various scrapie strains [RML ( Majer et al, 2012 ; Boese et al, 2016 ), 139A ( Gao et al, 2016 ), Me7 ( Gao et al, 2016 ) and 22A ( Saba et al, 2008 )] or scrapie infected SMB-S15 cells ( Gao et al, 2016 ), (d) murine hypothalamic GT1-7 cells infected with a mouse adapted human GSS strain ( Bellingham et al, 2012 ; Bellingham and Hill, 2017 ) and (e) murine neuroblastoma cells propagating the 22L scrapie strain ( Montag et al, 2012 ).…”

Regulation of MicroRNAs-Mediated Autophagic Flux: A New Regulatory Avenue for Neurodegenerative Diseases With Focus on Prion Diseases

“…miRNA-125 is upregulated in prion, AD, and PD models ( Cogswell et al, 2008 ; Bellingham et al, 2012 ; Cardo et al, 2013 ). Recently, Gao et al (2017) worked on miRNA expression profile of three prion strains, 139A, ME7, and S15. They found that the most significantly upregulated and downregulated miRNAs in scrapie-infected mice were, mmu-miRNA-3473e (9.48 log 2 ) and mmu-miRNA-141-5p (-7.33 log 2 ) in the 139A group, mmu-miRNA-3473e (13.18 log 2 ) and mmu-miRNA-200a-5p (-7.08 log 2 ) in the ME7 group, and mmu miRNA-3473e (14.15 log 2 ) and mmu-miRNA-183-3p (-10.15 log 2 ) in the S15 group ( Gao et al, 2017 ).…”

“…Recently, Gao et al (2017) worked on miRNA expression profile of three prion strains, 139A, ME7, and S15. They found that the most significantly upregulated and downregulated miRNAs in scrapie-infected mice were, mmu-miRNA-3473e (9.48 log 2 ) and mmu-miRNA-141-5p (-7.33 log 2 ) in the 139A group, mmu-miRNA-3473e (13.18 log 2 ) and mmu-miRNA-200a-5p (-7.08 log 2 ) in the ME7 group, and mmu miRNA-3473e (14.15 log 2 ) and mmu-miRNA-183-3p (-10.15 log 2 ) in the S15 group ( Gao et al, 2017 ). Recently, Burak et al (2018) demonstrated that miRNA-16 localized within the CA1 region of the hippocampus was upregulated in the early stage of prion infection.…”