Role of MicroRNAs, Aptamers in Neuroinflammation and Neurodegenerative Disorders

microRNA-146a-5p, Neurotropic Viral Infection and Prion Disease (PrD)

“…Among the most significant advances in human neuroscience, neurology and molecular neurogenetics over the last fifteen years are: (i) the discovery of a family of small noncoding single-stranded RNAs called microRNAs in the mammalian brain and cen-tral nervous system (CNS) and (ii) the analysis and categorization of their abundance, speciation and complexity in development, aging and in neurological health and CNS disease [2,5,6,9,70,71,93,101,107]. A growing body of evidence indicates that select species of the 2650 member human miRNA gene family are brain-abundant and participate in the initiation, propagation and development of insidious age-related neurological disorders of the mammalian brain and CNS.…”

“…All metazoan miRNAs appear to initially recognize their target mR-NAs by recognition of a 'seed region' or 'seed sequence' in the 3 -UTR; this 'seed region' is a conserved heptametrical sequence co-localized at positions 2-7 from the 5 -end of the miRNA. Even though base pairing of miRNA and its target mRNA often does not perfectly match, the 'seed sequence' is perfectly complementary [2,5,11]. In human neurodegenerative disease, miRNA-146a has several known relevant and verified targets that include the 3 -UTRs of: (i) the complement factor H (CFH) mRNA involved in inflammation and the innate immune response; (ii) the membrane-spanning TSPAN-12 protein involved in amyloidogenesis and the clearance of amyloid beta peptides from brain cells; and (iii) the interleukin-1 receptor kinase IRAK-1 (with a compensatory increase in IRAK-2) involved in pathological NF-kB accumulation, signaling and neuro-inflammation [2,[68][69][70][71].…”

“…The misfolded, abnormal and insoluble isoform of PrPc known as PrPsc self-associates into pro-inflammatory, protease-resistant aggregates that are insoluble in most detergents and chaotropic agents [59,75,84,[89][90][91]. The molecular mechanisms of PrPsc neurotoxicity that drive the initiation, development and progression of PrD are highly complex and, similar to the case of AD, increased oxidative stress and chronic inflammation appear to be critically involved in the initiation and progression of PrD [5,73,86,[92][93][94][95]. Typically, activated microglia accumulate within the immediate vicinity of abnormal PrPsc aggregates, and they release cytokines such as IL-1β that play important roles in the inflammatory pathogenesis of PrD, including the upregulation of genes that promote pro-inflammatory signaling and innate-immune system deficits [86,90].…”

“…As soluble, amphipathic regulatory molecules, miRNAs are important post-transcriptional and epigenetic regulators of messenger RNA (mRNA) abundance, speciation and complexity [1,2]. These microRNAs: (i) exist as~18-to~25-ribonucleotide (nt), single-stranded noncoding RNAs (sncRNAs) whose sequences are both unique and highly selected over evolution; (ii) represent the smallest information-carrying ribonucleic acids yet defined; (iii) have been repeatedly shown to play critical and determinant roles in the onset and propagation of many human CNS disorders, including progressive, incapacitating and terminal neurological syndromes; and (iv) are fascinating molecular entities because of their somewhat unconventional origin, their ribonucleotide sequence characteristics, their ability to regulate multiple cellular processes in health and disease, their immense potential in disease therapeutics and evolutionary dynamics [1,[3][4][5][6][7]. Regarding the evolutionary aspects of miRNA and miRNA sequence complexity and selection, from mathematical considerations alone, a~22 nt sncRNA with the possibility of four ribonucleotides at each position (A, C, G and U-adenine, cytosine, guanine and uracil, respectively) has the potential to generate an exponentiation of 4 to the power of 22 or about 1.76 × 10 13 unique miRNA species.…”

“…Interestingly, some miRNAs have been shown to maintain their exact or highly homologous miRNA ribonucleotide sequence between plants and animals over~1.5 billion years of evolution (the Arabidopsis thaliana-Homo sapiens divergence), indicating that highly conserved ribonucleotide sequence-mediated genetic regulatory functions are attributable to the same miRNAs and miRNA binding proteins over vast periods of time [1,8,9]. Further RNA-sequencing and array-based analyses have indicated that only certain miRNAs, probably about 25-30 individual miRNA species: (i) are abundant in the cytoplasm of the human brain as well as retinal and other CNS cells; (ii) are inducible by pathological factors, such as pro-inflammatory cytokines and chemokines; and (iii) are upregulated by different types of pathogenic microbes, including viral gene-encoded products and highly neurotoxic secreted bacterial exudates such as lipopolysaccharide (LPS) [5,10,11] see below.…”