Regional and subtype-dependent miRNA signatures in sporadic Creutzfeldt-Jakob disease are accompanied by alterations in miRNA silencing machinery and biogenesis
| Autor: | Natalia Fernández-Borges, Ana Vivancos, Eulàlia Martí, Katrin Thüne, Saima Zafar, Eirini Kanata, Inga Zerr, Juan María Torres, Theodoros Sklaviadis, Orr Shomroni, José Antonio del Río, Daniela Diaz-Lucena, Franc Llorens, Uwe Michel, Stefan Bonn, Dimitra Dafou, Andre Fischer, Olivier Andreoletti, Isidre Ferrer, Juana Díez, Matthias Schmitz |
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| Přispěvatelé: | Universitat de Barcelona, Georg-August-University [Göttingen], Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), German Center for Neurodegenerative Diseases, Center for Genomic Regulation, Aristotle University of Thessaloniki, Vall d'Hebron Institute of Oncology (VHIO), Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria = National Institute for Agricultural and Food Research and Technology (INIA), Interactions hôtes-agents pathogènes [Toulouse] (IHAP), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institute for Bioengineering of Catalonia [Barcelona] (IBEC), University of Barcelona, Centro de Regulación Genómica (CRG), Universitat Pompeu Fabra [Barcelona] (UPF), Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE) |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Micro RNAs Physiology biosynthesis [MicroRNAs] Biochemistry Nervous System Creutzfeldt-Jakob Syndrome 0302 clinical medicine pathology [Brain] RNA interference Zoonoses genetics [MicroRNAs] lcsh:QH301-705.5 Aged 80 and over Neurodegenerative diseases Neurodegeneration Microbiology and Parasitology Brain genetics [Creutzfeldt-Jakob Syndrome] Middle Aged Argonaute Alzheimer's disease Microbiologie et Parasitologie Body Fluids Nucleic acids [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology Cerebrospinal fluid Neurology Infectious diseases Female RNA Interference Anatomy Research Article Adult lcsh:Immunologic diseases. Allergy Prion diseases Immunology classification [Creutzfeldt-Jakob Syndrome] Médecine humaine et pathologie Biology Biosynthesis Microbiology 03 medical and health sciences Extraction techniques Virology Mental Health and Psychiatry microRNA Genetics medicine Humans Gene silencing ddc:610 Non-coding RNA Molecular Biology Aged Medicine and health sciences Fatal familial insomnia pathology [Creutzfeldt-Jakob Syndrome] Biology and life sciences Dementia with Lewy bodies Gene Expression Profiling medicine.disease Creutzfeldt-Jakob disease RNA extraction Gene regulation Research and analysis methods Gene expression profiling MicroRNAs 030104 developmental biology Malaltia d'Alzheimer lcsh:Biology (General) metabolism [Brain] Case-Control Studies RNA Dementia Parasitology Human health and pathology Gene expression Transcriptome lcsh:RC581-607 Neuroscience [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology 030217 neurology & neurosurgery |
| Zdroj: | PLoS Pathogens, Vol 14, Iss 1, p e1006802 (2018) Recercat. Dipósit de la Recerca de Catalunya instname Repositorio de Resultados de Investigación del INIA Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria INIA INIA: Repositorio de Resultados de Investigación del INIA Plos Pathogens 1 (14), e1006802. (2018) Dipòsit Digital de la UB Universidad de Barcelona PLoS pathogens 14(1), e1006802 (2018). doi:10.1371/journal.ppat.1006802 PLoS Pathogens PLoS Pathogens, Public Library of Science, 2018, 14 (1), pp.e1006802. ⟨10.1371/journal.ppat.1006802⟩ |
| ISSN: | 1553-7374 1553-7366 |
| DOI: | 10.1371/journal.ppat.1006802 |
| Popis: | Increasing evidence indicates that microRNAs (miRNAs) are contributing factors to neurodegeneration. Alterations in miRNA signatures have been reported in several neurodegenerative dementias, but data in prion diseases are restricted to ex vivo and animal models. The present study identified significant miRNA expression pattern alterations in the frontal cortex and cerebellum of sporadic Creutzfeldt-Jakob disease (sCJD) patients. These changes display a highly regional and disease subtype-dependent regulation that correlates with brain pathology. We demonstrate that selected miRNAs are enriched in sCJD isolated Argonaute(Ago)-binding complexes in disease, indicating their incorporation into RNA-induced silencing complexes, and further suggesting their contribution to disease-associated gene expression changes. Alterations in the miRNA-mRNA regulatory machinery and perturbed levels of miRNA biogenesis key components in sCJD brain samples reported here further implicate miRNAs in sCJD gene expression (de)regulation. We also show that a subset of sCJD-altered miRNAs are commonly changed in Alzheimer’s disease, dementia with Lewy bodies and fatal familial insomnia, suggesting potential common mechanisms underlying these neurodegenerative processes. Additionally, we report no correlation between brain and cerebrospinal fluid (CSF) miRNA-profiles in sCJD, indicating that CSF-miRNA profiles do not faithfully mirror miRNA alterations detected in brain tissue of human prion diseases. Finally, utilizing a sCJD MM1 mouse model, we analyzed the miRNA deregulation patterns observed in sCJD in a temporal manner. While fourteen sCJD-related miRNAs were validated at clinical stages, only two of those were changed at early symptomatic phase, suggesting that the miRNAs altered in sCJD may contribute to later pathogenic processes. Altogether, the present work identifies alterations in the miRNA network, biogenesis and miRNA-mRNA silencing machinery in sCJD, whereby contributions to disease mechanisms deserve further investigation. Author summary miRNAs are small non-coding RNAs that regulate gene expression through complementary binding to their mRNA targets. Specific miRNA signatures have been proposed for several neurodegenerative diseases supporting the idea that miRNA deregulation is a common disease hallmark. Here we present the comprehensive miRNA signature in sporadic Creutzfeldt-Jakob disease (sCJD). Our study unravels the complex network of regional and disease-subtype miRNA alterations, and the presence of a disturbed miRNA biogenesis pathway and miRNA-mRNA silencing machinery. We also highlight the existence of time-dependent miRNA profiles and identify commonly regulated miRNAs between several dementias with cortical pathology sharing a partial clinical overlap and pathological involvement with sCJD. The present data shed light on the potential role of miRNAs as a contributing factor of pathogenic molecular traits associated with sCJD. |
| Databáze: | OpenAIRE |
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