Pathogenic microRNAs Common to Brain and Retinal Degeneration; Recent Observations in Alzheimer’s Disease and Age-Related Macular Degeneration

摘要

MicroRNAs (miRNAs), ~22?nt single-stranded non-coding RNAs (ncRNAs) abundant in the human brain and retina, have emerged as significant post-transcriptional regulators of messenger RNA (mRNA) abundance and complexity in the human central nervous system (CNS) in aging, health, and disease. Of the 2050 different miRNAs in the human body so far identified, only about 25–30 are abundant in either the brain or the retina, underscoring the high selection pressure carried by RNA sequences located within these select ncRNAs ( 1 – 7 ). It is noteworthy to point out that: (i) that brain neocortex and retina share a common neuroectodermal origin; (ii) that brain and retina share a subfamily of specific miRNA species; and (iii) that the multilayered assemblies of both neural and retinal cells are targeted by pathogenic processes that drive progressive pro-inflammatory neurodegeneration ( 5 – 9 ). Indeed, pathologically up-regulated miRNAs common to both the prototypic age-related inflammatory degeneration of the brain in Alzheimer’s disease (AD) and of the retina in age-related macular degeneration (AMD) appear to be associated with deficits in the expression of messenger RNA (mRNA) and gene families involved in the innate-immune response, inflammation, neurotrophism, synaptogenesis, and amyloidogenesis (Figure 1 ). In this “Opinion” paper for the Frontiers in Neurology Special Research Topic , we will highlight some of the most recent work in this research area, with emphasis on a family of five up-regulated pro-inflammatory miRNAs?–?miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a, and miRNA-155?–?that are emerging as key mechanistic contributors to the AD and AMD process. Figure 1 (A) Color-coded cluster analysis of significantly up-regulated microRNAs (miRNAs) in the neocortex of AD ( N ?=?5) versus age-matched controls ( N ?=?5) and (B) in the whole retina of AMD ( N ?=?5) versus age-matched controls ( N ?=?5); this small family of “pro-inflammatory” miRNAs consisting of miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a, and miRNA-155 are often found to be up-regulated approximately twofold or more over controls (small red arrows); interestingly these miRNAs are inducible and under transcriptional control by NF-kB [Figure 1 adapted from Ref. ( 10 – 13 )]; the relative expression levels for two sequence-related microRNAs, miRNA-146a and miRNA-155 the brain neocortex and retina are shown in (C) relative to levels for an unchanging brain and retinal control miRNA-183, which was set to 1.0 and marked by a dashed horizontal line; another abundant control signal is 5SRNA with a relative signal strength of ~5.0 (shown at ~1/20th of its actual abundance in the brain and retina; see text) ( 12 , 13 ). In these samples, all control and AD neocortical samples were obtained from the superior temporal neocortex (Brodmann area A22); control and AMD retinal samples were obtained from whole retina; all control, AD and AMD samples had post-mortem intervals (PMI; death to brain freezing interval) of 2?h or less ( 2 , 9 , 10 ). Controls were age-matched to moderate-to-late stages of AD or AMD; increases in specific miRNAs increased as disease stage advanced [Ref. ( 11 , 12 , 14 – 17 ); data not shown]; further details on the pathology of these samples have been recently published ( 11 – 20 ). There were no significant differences in age, PMI, or RNA yield or quality between either the brain or the retinal tissues. Of the 12 different homo sapien micro-RNAs (hsa-miRNAs) shown, miRNA-146a and miRNA-155 exhibited the most consistent up-regulation compared with age-matched controls (* p ?