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Changes in the miRNA-mRNA Regulatory Network Precede Motor Symptoms in a Mouse Model of Multiple System Atrophy: Clinical Implications

Multiple system atrophy (MSA) is a fatal rapidly progressive α-synucleinopathy, characterized by α-synuclein accumulation in oligodendrocytes. It is accepted that the pathological α-synuclein accumulation in the brain of MSA patients plays a leading role in the disease process, but little is known a...

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Autores principales: Schafferer, Simon, Khurana, Rimpi, Refolo, Violetta, Venezia, Serena, Sturm, Edith, Piatti, Paolo, Hechenberger, Clara, Hackl, Hubert, Kessler, Roman, Willi, Michaela, Gstir, Ronald, Krogsdam, Anne, Lusser, Alexandra, Poewe, Werner, Wenning, Gregor K., Hüttenhofer, Alexander, Stefanova, Nadia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786272/
https://www.ncbi.nlm.nih.gov/pubmed/26962858
http://dx.doi.org/10.1371/journal.pone.0150705
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author Schafferer, Simon
Khurana, Rimpi
Refolo, Violetta
Venezia, Serena
Sturm, Edith
Piatti, Paolo
Hechenberger, Clara
Hackl, Hubert
Kessler, Roman
Willi, Michaela
Gstir, Ronald
Krogsdam, Anne
Lusser, Alexandra
Poewe, Werner
Wenning, Gregor K.
Hüttenhofer, Alexander
Stefanova, Nadia
author_facet Schafferer, Simon
Khurana, Rimpi
Refolo, Violetta
Venezia, Serena
Sturm, Edith
Piatti, Paolo
Hechenberger, Clara
Hackl, Hubert
Kessler, Roman
Willi, Michaela
Gstir, Ronald
Krogsdam, Anne
Lusser, Alexandra
Poewe, Werner
Wenning, Gregor K.
Hüttenhofer, Alexander
Stefanova, Nadia
author_sort Schafferer, Simon
collection PubMed
description Multiple system atrophy (MSA) is a fatal rapidly progressive α-synucleinopathy, characterized by α-synuclein accumulation in oligodendrocytes. It is accepted that the pathological α-synuclein accumulation in the brain of MSA patients plays a leading role in the disease process, but little is known about the events in the early stages of the disease. In this study we aimed to define potential roles of the miRNA-mRNA regulatory network in the early pre-motor stages of the disease, i.e., downstream of α-synuclein accumulation in oligodendroglia, as assessed in a transgenic mouse model of MSA. We investigated the expression patterns of miRNAs and their mRNA targets in substantia nigra (SN) and striatum, two brain regions that undergo neurodegeneration at a later stage in the MSA model, by microarray and RNA-seq analysis, respectively. Analysis was performed at a time point when α-synuclein accumulation was already present in oligodendrocytes at neuropathological examination, but no neuronal loss nor deficits of motor function had yet occurred. Our data provide a first evidence for the leading role of gene dysregulation associated with deficits in immune and inflammatory responses in the very early, non-symptomatic disease stages of MSA. While dysfunctional homeostasis and oxidative stress were prominent in SN in the early stages of MSA, in striatum differential gene expression in the non-symptomatic phase was linked to oligodendroglial dysfunction, disturbed protein handling, lipid metabolism, transmembrane transport and altered cell death control, respectively. A large number of putative miRNA-mRNAs interaction partners were identified in relation to the control of these processes in the MSA model. Our results support the role of early changes in the miRNA-mRNA regulatory network in the pathogenesis of MSA preceding the clinical onset of the disease. The findings thus contribute to understanding the disease process and are likely to pave the way towards identifying disease biomarkers for early diagnosis of MSA.
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spelling pubmed-47862722016-03-23 Changes in the miRNA-mRNA Regulatory Network Precede Motor Symptoms in a Mouse Model of Multiple System Atrophy: Clinical Implications Schafferer, Simon Khurana, Rimpi Refolo, Violetta Venezia, Serena Sturm, Edith Piatti, Paolo Hechenberger, Clara Hackl, Hubert Kessler, Roman Willi, Michaela Gstir, Ronald Krogsdam, Anne Lusser, Alexandra Poewe, Werner Wenning, Gregor K. Hüttenhofer, Alexander Stefanova, Nadia PLoS One Research Article Multiple system atrophy (MSA) is a fatal rapidly progressive α-synucleinopathy, characterized by α-synuclein accumulation in oligodendrocytes. It is accepted that the pathological α-synuclein accumulation in the brain of MSA patients plays a leading role in the disease process, but little is known about the events in the early stages of the disease. In this study we aimed to define potential roles of the miRNA-mRNA regulatory network in the early pre-motor stages of the disease, i.e., downstream of α-synuclein accumulation in oligodendroglia, as assessed in a transgenic mouse model of MSA. We investigated the expression patterns of miRNAs and their mRNA targets in substantia nigra (SN) and striatum, two brain regions that undergo neurodegeneration at a later stage in the MSA model, by microarray and RNA-seq analysis, respectively. Analysis was performed at a time point when α-synuclein accumulation was already present in oligodendrocytes at neuropathological examination, but no neuronal loss nor deficits of motor function had yet occurred. Our data provide a first evidence for the leading role of gene dysregulation associated with deficits in immune and inflammatory responses in the very early, non-symptomatic disease stages of MSA. While dysfunctional homeostasis and oxidative stress were prominent in SN in the early stages of MSA, in striatum differential gene expression in the non-symptomatic phase was linked to oligodendroglial dysfunction, disturbed protein handling, lipid metabolism, transmembrane transport and altered cell death control, respectively. A large number of putative miRNA-mRNAs interaction partners were identified in relation to the control of these processes in the MSA model. Our results support the role of early changes in the miRNA-mRNA regulatory network in the pathogenesis of MSA preceding the clinical onset of the disease. The findings thus contribute to understanding the disease process and are likely to pave the way towards identifying disease biomarkers for early diagnosis of MSA. Public Library of Science 2016-03-10 /pmc/articles/PMC4786272/ /pubmed/26962858 http://dx.doi.org/10.1371/journal.pone.0150705 Text en © 2016 Schafferer et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Schafferer, Simon
Khurana, Rimpi
Refolo, Violetta
Venezia, Serena
Sturm, Edith
Piatti, Paolo
Hechenberger, Clara
Hackl, Hubert
Kessler, Roman
Willi, Michaela
Gstir, Ronald
Krogsdam, Anne
Lusser, Alexandra
Poewe, Werner
Wenning, Gregor K.
Hüttenhofer, Alexander
Stefanova, Nadia
Changes in the miRNA-mRNA Regulatory Network Precede Motor Symptoms in a Mouse Model of Multiple System Atrophy: Clinical Implications
title Changes in the miRNA-mRNA Regulatory Network Precede Motor Symptoms in a Mouse Model of Multiple System Atrophy: Clinical Implications
title_full Changes in the miRNA-mRNA Regulatory Network Precede Motor Symptoms in a Mouse Model of Multiple System Atrophy: Clinical Implications
title_fullStr Changes in the miRNA-mRNA Regulatory Network Precede Motor Symptoms in a Mouse Model of Multiple System Atrophy: Clinical Implications
title_full_unstemmed Changes in the miRNA-mRNA Regulatory Network Precede Motor Symptoms in a Mouse Model of Multiple System Atrophy: Clinical Implications
title_short Changes in the miRNA-mRNA Regulatory Network Precede Motor Symptoms in a Mouse Model of Multiple System Atrophy: Clinical Implications
title_sort changes in the mirna-mrna regulatory network precede motor symptoms in a mouse model of multiple system atrophy: clinical implications
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786272/
https://www.ncbi.nlm.nih.gov/pubmed/26962858
http://dx.doi.org/10.1371/journal.pone.0150705
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