This study provides evidence of upregulation of miRNA-146a in extremely rare (incidence 1–10 per 100 million) human prion-based neurodegenerative disorders, including sporadic Creutzfeldt–Jakob disease (sCJD) and Gerstmann–Straussler–Scheinker syndrome (GSS). The findings suggest that an upregulated miRNA-146a may be integral to innate immune or inflammatory brain cell responses in prion-mediated infections and to progressive and irreversible neurodegeneration of both the murine and human brain.
Abundance of hsa-miRNA-125b and/or hsa-miRNA-146a in comparison to an internal control hsa-5S RNA marker in murine scrapie 139a, sporadic Creutzfeldt–Jakob disease (sCJD), and Gerstmann–Straussler–Scheinker syndrome (GSS) compared to age-matched controls (control) in the same brain region as analyzed by (A) fluorescent miRNA array cluster analysis (LC Sciences, Houston TX) and (B) concentrated Northern dot-blot analysis of 5S RNA and miRNA-146a using high-specific-activity radiolabeled probes (Cui et al. 2005; Sethi and Lukiw 2009); (C) quantified results from Northern dot-blot analysis; dashed horizontal line indicates control 139A levels relative to 5S RNA for ease of comparison. In (A) panel 1 is the age-matched control for murine 139a (n = 2; lanes 4 and 5); lanes 2 and 3 are the mean age-matched control for the individual cases for sCJD (n = 3; lanes 6–8) and GSS (n = 2, lanes 9 and 10), respectively; by convention, green colors indicate no change and red colors indicate upregulation (LC Sciences; Lukiw et al. 2008). Squared black lines to the left of panel (A) indicate that a mean signal intensity comparison between hsa-5S-RNA and hsa-miRNA-125b yielded a significance of p > .07 (ANOVA), and between 5S-RNA and hsa-miRNA-146a yielded a p < .01 (ANOVA). miRNA-125b was found to be significantly upregulated in one of two GSS cases and two of three CJD cases; miRNA-146a was found to be consistently elevated in all sCJD or GSS cases using miRNA array analysis; and this was further confirmed using quantitative Northern dot blot analysis (B and C). The 22 nucleotide hsa-5S-RNA probe was derived from the 5 end of the 107 nucleotide human 5S ribosomal RNA (5S RNA) and in panel (B) was loaded at 1/10 the concentration of miRNA-146a (Sethi and Lukiw 2009) (color figure available online).
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Lukiw WJ, Dua P, Pogue AI, Eicken C, Hill JM. (2011) “Upregulation of Micro RNA-146a (miRNA-146a), A Marker for Inflammatory Neurodegeneration, in Sporadic Creutzfeldt-Jakob Disease (sCJD) and Gerstmann-Straussler-Scheinker (GSS) Syndrome”. J Toxicol Environ Health A 74(22-24), 1460-8. [abstract]