Huntingtin Aggregation Impairs Autophagy, Leading to Argonaute-2 Accumulation and Global MicroRNA Dysregulation.
Autor: | Pircs K; Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, 221 84 Lund, Sweden., Petri R; Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, 221 84 Lund, Sweden., Madsen S; Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, 221 84 Lund, Sweden., Brattås PL; Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, 221 84 Lund, Sweden., Vuono R; John van Geest Centre for Brain Repair and Department of Neurology, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Cambridge CB2 0PY, UK., Ottosson DR; Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, 221 84 Lund, Sweden., St-Amour I; Axe Neurosciences, Centre de Recherche du CHU de Québec - Université Laval, CHUL, Québec, QC G1V 4G2, Canada., Hersbach BA; Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, 221 84 Lund, Sweden., Matusiak-Brückner M; Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, 221 84 Lund, Sweden., Lundh SH; Translational Neuroendocrine Research Unit (TNU), Department of Experimental Medical Science, Wallenberg Neuroscience Center, BMC D11, Lund University, 221 84 Lund, Sweden., Petersén Å; Translational Neuroendocrine Research Unit (TNU), Department of Experimental Medical Science, Wallenberg Neuroscience Center, BMC D11, Lund University, 221 84 Lund, Sweden., Déglon N; Laboratory of Cellular and Molecular Neurotherapies (LCMN), Department of Clinical Neuroscience (DNC), Neuroscience Research Center (CRN), Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland., Hébert SS; Axe Neurosciences, Centre de Recherche du CHU de Québec - Université Laval, CHUL, Québec, QC G1V 4G2, Canada., Parmar M; Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, 221 84 Lund, Sweden., Barker RA; John van Geest Centre for Brain Repair and Department of Neurology, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Cambridge CB2 0PY, UK; Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, 221 84 Lund, Sweden., Jakobsson J; Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, 221 84 Lund, Sweden. Electronic address: johan.jakobsson@med.lu.se. |
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Jazyk: | angličtina |
Zdroj: | Cell reports [Cell Rep] 2018 Aug 07; Vol. 24 (6), pp. 1397-1406. |
DOI: | 10.1016/j.celrep.2018.07.017 |
Abstrakt: | Many neurodegenerative diseases are characterized by the presence of intracellular protein aggregates, resulting in alterations in autophagy. However, the consequences of impaired autophagy for neuronal function remain poorly understood. In this study, we used cell culture and mouse models of huntingtin protein aggregation as well as post-mortem material from patients with Huntington's disease to demonstrate that Argonaute-2 (AGO2) accumulates in the presence of neuronal protein aggregates and that this is due to impaired autophagy. Accumulation of AGO2, a key factor of the RNA-induced silencing complex that executes microRNA functions, results in global alterations of microRNA levels and activity. Together, these results demonstrate that impaired autophagy found in neurodegenerative diseases not only influences protein aggregation but also directly contributes to global alterations of intracellular post-transcriptional networks. (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.) |
Databáze: | MEDLINE |
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