MicroRNA (miRNA): Sequence and stability, viroid-like properties, and disease association in the CNS

Abstract

MicroRNAs (miRNAs) constitute a relatively recently-discovered class of small non-coding RNAs (sncRNAs) that are gaining considerable attention in the molecular-genetic regulatory mechanisms that contribute to human health and disease. As highly soluble and mobile entities, emerging evidence indicates that miRNAs posess a highly selected ribonucleotide sequence structure, are part of an evolutionary ancient genetic signaling system, resemble the plant pathogens known as viroids in their structure, mode of generation and function, and are very abundant in the physiological fluids that surround cells and tissues. Persistence and altered abundance of miRNAs in the extracellular fluid (ECF) or cerebrospinal fluid (CSF) may play a role in the intercellular spreading of disease systemically, and throughout functionally-linked cellular and tissue systems such as the central nervous system (CNS). This short communication will review some of the more fascinating features of these highly structured single stranded RNAs (ssRNAs) with emphasis on their presence and function in the human CNS, with particular reference to Alzheimer's disease (AD) wherever possible.

Influence of Extracellular RNAs, Released by Rheumatoid Arthritis Synovial Fibroblasts, on Their Adhesive and Invasive Properties

“…A s an endogenous alarm signal, eukaryotic extracellular RNA (exRNA) has been detected in the extracellular space of tissues, in plasma, cerebrospinal fluid, saliva, urine, and seminal fluid (1)(2)(3)(4)(5), and promotes immunoregulatory, procoagulatory, and vessel permeability-regulating functions (6)(7)(8)(9). Moreover, following cell activation, exRNA was found enriched in supernatants of human leukocytes, epithelial cells, cardiomyocytes, and various tumor cells (10)(11)(12)(13).…”

microRNA (miRNA)-Mediated Pathogenetic Signaling in Alzheimer’s Disease (AD)

“…Similar to the biophysical nucleotide parameters that govern the half-life of messenger RNA (mRNA) molecules, miRNAs appear to follow many of the same stability rules involving adenine-uridine (AU) rich elements, termed 'AREs' in their linear dimension [17][18][19][20][21][22]. This generally means that a higher content of AREs in miRNAs is associated with a reduced miRNA half-life, and a deficiency in AU or UA dinucleotides or increase in the presence of ribonuclease-shielding by ARE binding proteins (AREBPs) may confer increased miRNA stability, and these have been shown to lengthen miRNA half-life both in vitro and in vivo [21][22][23][24][25].…”

“…To cite just one example using novel genome-wide computational approaches to detect miRNAs based on both sequence and structure alignments, the miRNA-854 family has been shown to be expressed in Arabidopsis thaliana, Caenorhabditis elegans, Mus musculus, and Homo sapiens. Within each of these diverse species (Arabidopsis-Homo sapiens divergence about *1.5 9 10 9 years) miRNA-854 commonly targets an oligouridylate binding protein1b mRNA 3 0 UTR that normally encodes a member of a heterogeneous nuclear RNA binding protein (hnRNP) which serves as a basal regulator eukaryotic transcription [16,17,29]. Moreover, secondary structures also appear to be conserved between multiple miRNAs and internal stems, loops and mis-paired ssRNA 'bulges' that are evident in identical positions in many premiRNA sequences [25][26][27][28][29][30][31].…”

“…Importantly it appears that the abundance, speciation and complexity of these highly selected miRNAs may vary amongst different human populations in aging, health and neurological disease [11][12][13][14][15]. A number of very recent and excellent papers concerning the altered miRNA abundance, speciation and complexity in AD and the aging CNS have recently appeared in the literature and will not be dealt with further here, but interested readers are encouraged to refer to these very recent reports and their content and interpretation [12][13][14][15][16][17][18][19][20].…”

“…As there are typically so far identified only about 2 9 10 3 different mature miRNAs in humans suggest an extremely high evolutionary selection pressure to utilize only specific ribonucleotide sequences that will yield biologically productive miRNAmRNA interactions [12][13][14][15]. Indeed, few places in all of human genome biology are there so high an informationdense network of epigenetic regulatory control as in the CNS family of miRNAs [15][16][17][18][19]. Further to this idea, direct RNA-sequencing-, RT-PCR-, Northern dot blot and miRNA array-based analyses indicate that high abundance miRNAs in the human CNS probably number less than about *45 different miRNA species, and remarkably, only a smaller fraction of these appear to be progressively altered in abundance in AD affected tissues [12][13][14][15][16].…”