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

Abstract

The human brain and central nervous system (CNS) harbor a select sub-group of potentially pathogenic microRNAs (miRNAs), including a well-characterized NF-kB-sensitive Homo sapiens microRNA hsa-miRNA-146a-5p (miRNA-146a). miRNA-146a is significantly over-expressed in progressive and often lethal viral- and prion-mediated and related neurological syndromes associated with progressive inflammatory neurodegeneration. These include ~18 different viral-induced encephalopathies for which data are available, at least ~10 known prion diseases (PrD) of animals and humans, Alzheimer’s disease (AD) and other sporadic and progressive age-related neurological disorders. Despite the apparent lack of nucleic acids in prions, both DNA- and RNA-containing viruses along with prions significantly induce miRNA-146a in the infected host, but whether this represents part of the host’s adaptive immunity, innate-immune response or a mechanism to enable the invading prion or virus a successful infection is not well understood. Current findings suggest an early and highly interactive role for miRNA-146a: (i) as a major small noncoding RNA (sncRNA) regulator of innate-immune responses and inflammatory signaling in cells of the human brain and CNS; (ii) as a critical component of the complement system and immune-related neurological dysfunction; (iii) as an inducible sncRNA of the brain and CNS that lies at a critical intersection of several important neurobiological adaptive immune response processes with highly interactive associations involving complement factor H (CFH), Toll-like receptor pathways, the innate-immunity, cytokine production, apoptosis and neural cell decline; and (iv) as a potential biomarker for viral infection, TSE and AD and other neurological diseases in both animals and humans. In this report, we review the recent data supporting the idea that miRNA-146a may represent a novel and unique sncRNA-based biomarker for inflammatory neurodegeneration in multiple species. This paper further reviews the current state of knowledge regarding the nature and mechanism of miRNA-146a in viral and prion infection of the human brain and CNS with reference to AD wherever possible.

microRNA, the Innate-Immune System and SARS-CoV-2

“…Possessing an unusually large, positive-sense, ssvRNA genome of about ~29,903 nucleotides (nt; SARS-CoV-2 isolate Wuhan-Hu-1, Ke et al, 2020 ; Sah et al, 2020 ; Wu et al, 2020 ; Mousavizadeh and Ghasemi, 2021 ; National Center for Biological Information (NCBI) GenBank Accession No. NC_045512.2; last accessed 16 May 2022 ), SARS-CoV-2: (i) is a member of the genus Betacoronavirus in the family Coronaviridae that includes other common pathogenic human influenza-causing ssvRNA Coronaviruses (hCoV-OC43, HKU1 and 229E), SARS and MERS-CoV ( Sah et al, 2020 ; Mousavizadeh and Ghasemi, 2021 ; Raghuvamsi et al, 2021 ); (ii) consists of a nucleocapsid core containing genomic ssvRNA within a lipoprotein envelope forming a ~100 nm diameter spherical virion particle ( Ke et al, 2020 ); (iii) structurally resembles a ‘typical’ large messenger RNA (mRNA) possessing a 5′ methyl cap structure, a 3′ poly(A) tail and ~10-14 overlapping open reading frames (ORFs) with minimal spacer regions, encoding ~29 proteins, not all of which have been fully characterized ( Ke et al, 2020 ; Sah et al, 2020 ; Raghuvamsi et al, 2021 ); (iv) possesses one of the largest ssvRNA genomes of all known ssvRNA viruses and a correspondingly huge target for potential sncRNA and miRNA interaction ( Finkel et al, 2021 ; Mousavizadeh and Ghasemi, 2021 ; Pogue and Lukiw, 2021 ; Lukiw, 2022 ); (v) as an ssvRNA virus is representative of the most common type of emerging viral disease in humans; this appears to be attributable to the high mutation rate in RNA viruses (compared to DNA viruses) that possess extremely high mutation rates of up to 10 6 times higher than that of their hosts ( Pachetti et al, 2020 ); and (vi) orchestrates a multipronged strategy to impede host protein synthesis including the accelerated degradation of host cytosolic cellular mRNAs, thus facilitating viral takeover of the host mRNA pool in infected cells ( Finkel et al, 2021 ; Lukiw, 2022 ). The main structural proteins of SARS-CoV-2 include the envelope (‘E’), membrane (‘M’), nucleocapsid (‘N’), replicase (‘R’; an RNA dependent RNA polymerase or RdRp), surface spike (‘S’) protein and several accessory viral-encoded proteins ( Ke et al., 2020 ; Finkel et al., 2021 ; Siniscalchi et al., 2021 ).…”

microRNA-146a as a biomarker for transmissible spongiform encephalopathy

“…What is essential in successful human TSE diagnosis is the integrated knowledge and assessment of multiple biomarkers and interrelated factors that include the patient's age, gender and lifestyle, family, medical, genetic and clinical history, cognitive, physical, behavioral and geriatric assessment, laboratory examination of multiple biofluids, especially within the systemic circulation (lymphatics, glymphatics and blood serum) and CSF, and multiple neuroimaging-modalities of the brain's cortex and/or limbic system compared to unaffected control regions within the same brain [45,50]. For example there is evidence that miRNA-146a is induced by at least 18 single-stranded RNA (ssRNA) or double-stranded DNA (dsDNA) neurotropic viruses including SARS-CoV-2, the causative agent of COVID-19 [37]. Clinical treatment of suspected TSE patients with broad spectrum antiviral and/or antimicrobial medications and/or vaccines might help exclude a diagnosis of viral involvement in suspected PrD.…”

Fission Impossible: Stabilized miRNA-Based Analogs in Neurodegenerative Disease

“…The significant heterogeneity in the presentation of AD is based in part on individual variation in genetics, genetic and familial history, the abundance and speciation of different SP and NFT isoforms in anatomical regions of the brain involved with cognition and memory, the Braak stage of the disease, the environment, diet and lifestyle, inter-current illness, multiple parameters associated with gender and aging and other factors associated with the intrinsic complexity of the disease itself (DeTure and Dickson, 2019 ; Habes et al, 2020 ). Since the first reported alterations of miRNA abundance, speciation and complexity in the affected regions of AD brain much research attention has been placed on: (i) the abundance, speciation, stability and lability of brain-enriched miRNAs; and (ii) how miRNA patterns are altered during the initiation and propagation of the neurodegenerative disease process as is observed both in affected AD tissues and in transgenic murine research models for AD (TgAD; Lukiw, 2007 ; Sobue, 2013 ; Bouter et al, 2020 ; Zhao et al, 2020 ; Lauretti et al, 2021 ; Pogue and Lukiw, 2021 ; Tasker et al, 2021 ).…”

“…The discovery and characterization of miRNAs, their temporal fluctuation in abundance and their biological actions in the developing, aging, and pathological human brain and CNS has opened a novel and fascinating vista into our appreciation of human brain epigenetics, the role of sncRNAs on homeostatic and pathogenic gene control and the potential role of sncRNA signals in modulating the genetic output of the human CNS (Guo et al, 2010 ; Bartel, 2018 ; Zhao et al, 2020 ; Pogue and Lukiw, 2021 ). Accordingly miRNAs, as the smallest known information-containing ribonucleic acids yet described, are associated with multiple cellular processes and the up-or down-regulation of miRNAs appears to be causative for numerous diseases including cancer, inflammation, cardiovascular disease and neurological disorders.…”

“…miRNA profiles in the brains of neurodegenerative disease patients are widely documented to be significantly altered compared to healthy age-matched controls, often in a disease stage- and/or anatomically-specific manner and correlated with the neuropathological anatomy of the disease. In AD, how these specific alterations in miRNA abundance, speciation and complexity impact disease initiation, propagation and severity and whether they are the result, cause or effect, along the trajectory of this heterogeneous and complex disease in most cases remains unclear (Colangelo et al, 2002 ; Lukiw, 2007 ; Herrera-Espejo et al, 2019 ; Kinoshita et al, 2021 ; Li and Cai, 2021 ; Liang et al, 2021 ; Pogue and Lukiw, 2021 ). Specific drug targeting issues and complications can be overcome by extensive experimentation involving testing with differentially stabilized miRNAs, antagomirs and related anti-ribonuclease strategies, the updating and constant refinement of miRNA-based therapeutic approaches and by novel miRNA and/or antagomir delivery protocols using TgAD models as a guide (Kinoshita et al, 2021 ; Liang and Wang, 2021 ; Liang et al, 2021 ; Nguyen et al, 2021 ; Zhang et al, 2021 ).…”