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      MicroRNA Alterations in a Tg501 Mouse Model of Prion Disease

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          Abstract

          MicroRNAs (miRNAs) may contribute to the development and pathology of many neurodegenerative diseases, including prion diseases. They are also promising biomarker candidates due to their stability in body fluids. We investigated miRNA alterations in a Tg501 mouse model of prion diseases that expresses a transgene encoding the goat prion protein ( PRNP). Tg501 mice intracranially inoculated with mouse-adapted goat scrapie were compared with age-matched, mock inoculated controls in preclinical and clinical stages. Small RNA sequencing from the cervical spinal cord indicated that miR-223-3p, miR-151-3p, and miR-144-5p were dysregulated in scrapie-inoculated animals before the onset of symptoms. In clinical-stage animals, 23 significant miRNA alterations were found. These miRNAs were predicted to modify the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways including prion disease, extracellular matrix interactions, glutaminergic synapse, axon guidance, and transforming growth factor-beta signaling. MicroRNAs miR-146a-5p (up in cervical spinal cord) and miR-342-3p (down in cervical spinal cord, cerebellum and plasma), both indicated in neurodegenerative diseases earlier, were verified by quantitative real-time polymerase chain reaction (qRT-PCR). Minimal changes observed before the disease onset suggests that most miRNA alterations observed here are driven by advanced prion-associated pathology, possibly limiting their use as diagnostic markers. However, the results encourage further mechanistic studies on miRNA-regulated pathways involved in these neurodegenerative conditions.

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          Most cited references 51

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          Small RNA deep sequencing reveals a distinct miRNA signature released in exosomes from prion-infected neuronal cells

          Prion diseases are transmissible neurodegenerative disorders affecting both humans and animals. The cellular prion protein, PrPC, and the abnormal infectious form, PrPSc, are found associated with exosomes, which are small 50–130 nm vesicles released from cells. Exosomes also contain microRNAs (miRNAs), a class of non-coding RNA, and have been utilized to identify miRNA signatures for diagnosis of disease. While some miRNAs are deregulated in prion-infected brain tissue, the role of miRNA in circulating exosomes released during prion disease is unknown. Here, we investigated the miRNA profile in exosomes released from prion-infected neuronal cells. We performed the first small RNA deep sequencing study of exosomes and demonstrated that neuronal exosomes contain a diverse range of RNA species including retroviral RNA repeat regions, messenger RNA fragments, transfer RNA fragments, non-coding RNA, small nuclear RNA, small nucleolar RNA, small cytoplasmic RNA, silencing RNA as well as known and novel candidate miRNA. Significantly, we show that exosomes released by prion-infected neuronal cells have increased let-7b, let-7i, miR-128a, miR-21, miR-222, miR-29b, miR-342-3p and miR-424 levels with decreased miR-146 a levels compared to non-infected exosomes. Overall, these results demonstrate that circulating exosomes released during prion infection have a distinct miRNA signature that can be utilized for diagnosis and understanding pathogenic mechanisms in prion disease.
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            NLRP3 inflammasome activity is negatively controlled by miR-223.

            Inflammasomes are multiprotein signaling platforms that form upon sensing microbe- or damage-associated molecular patterns. Upon their formation, caspase-1 is activated, leading to the processing of certain proinflammatory cytokines and the initiation of a special type of cell death, known as pyroptosis. Among known inflammasomes, NLRP3 takes on special importance because it appears to be a general sensor of cell stress. Moreover, unlike other inflammasome sensors, NLRP3 inflammasome activity is under additional transcriptional regulation. In this study, we identify the myeloid-specific microRNA miR-223 as another critical regulator of NLRP3 inflammasome activity. miR-223 suppresses NLRP3 expression through a conserved binding site within the 3' untranslated region of NLRP3, translating to reduced NLRP3 inflammasome activity. Although miR-223 itself is not regulated by proinflammatory signals, its expression varies among different myeloid cell types. Therefore, given the tight transcriptional control of NLRP3 message itself, miR-223 functions as an important rheostat controlling NLRP3 inflammasome activity.
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              • Abstract: found
              • Article: not found

              Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice.

              To investigate miR-155 in the SOD1 mouse model and human sporadic and familial amyotrophic lateral sclerosis (ALS).
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                Author and article information

                Journal
                Biomolecules
                Biomolecules
                biomolecules
                Biomolecules
                MDPI
                2218-273X
                15 June 2020
                June 2020
                : 10
                : 6
                Affiliations
                [1 ]Laboratorio de Genética Bioquímica (LAGENBIO), Facultad de Veterinaria, University of Zaragoza, 50013 Zaragoza, Spain; davidsanzrubio91@ 123456gmail.com (D.S.-R.); oscarlzpz@ 123456gmail.com (Ó.L.-P.); osta@ 123456unizar.es (R.O.); pilarzar@ 123456unizar.es (P.Z.); minma@ 123456unizar.es (I.M.-B.)
                [2 ]Instituto de Investigación Sanitaria Aragón (IIS Aragón), University of Zaragoza, 50009 Zaragoza, Spain
                [3 ]Instituto Agroalimentario de Aragón (IA2) University of Zaragoza-CITA, 50013 Zaragoza, Spain
                [4 ]The Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Institute Carlos III, 28031 Madrid, Spain
                [5 ]Centro de Encefalopatías y Enfermedades Transmisibles Emergentes, University of Zaragoza, 50013 Zaragoza, Spain; rbolea@ 123456unizar.es (R.B.); badiola@ 123456unizar.es (J.J.B.)
                [6 ]Instituto de Investigación Biomédica de Bellvitge (IDIBELL), 08908 Barcelona, Spain
                [7 ]Centro de Investigación en Sanidad Animal (CISA-INIA), 28130 Madrid, Spain; marin.alba@ 123456inia.es (A.M.-M.); espinosa.juan@ 123456inia.es (J.-C.E.); jmtorres@ 123456inia.es (J.-M.T.)
                Author notes
                [* ]Correspondence: toivonen@ 123456unizar.es
                Article
                biomolecules-10-00908
                10.3390/biom10060908
                7355645
                32549330
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                Categories
                Article

                biomarkers, microrna, scrapie, prion diseases

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