title: Changes in the miRNA-mRNA Regulatory Network Precede Motor Symptoms in a Mouse Model of Multiple System Atrophy: Clinical Implications.
abstract: 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.
authors.affiliation: Division of Genomics and RNomics, Biocenter, Medical University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Simon
authors.initials: S
authors.lastname: Schafferer
authors.affiliation: Division of Genomics and RNomics, Biocenter, Medical University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Rimpi
authors.initials: R
authors.lastname: Khurana
authors.affiliation: Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, Innrain 66/G2, 6020 Innsbruck, Austria.
authors.forename: Violetta
authors.initials: V
authors.lastname: Refolo
authors.affiliation: Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, Innrain 66/G2, 6020 Innsbruck, Austria.
authors.forename: Serena
authors.initials: S
authors.lastname: Venezia
authors.affiliation: Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, Innrain 66/G2, 6020 Innsbruck, Austria.
authors.forename: Edith
authors.initials: E
authors.lastname: Sturm
authors.affiliation: Division of Molecular Biology, Biocenter, Medical University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Paolo
authors.initials: P
authors.lastname: Piatti
authors.affiliation: Division of Molecular Biology, Biocenter, Medical University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Clara
authors.initials: C
authors.lastname: Hechenberger
authors.affiliation: Division of Bioinformatics, Biocenter, Medical University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Hubert
authors.initials: H
authors.lastname: Hackl
authors.affiliation: Division of Genomics and RNomics, Biocenter, Medical University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Roman
authors.initials: R
authors.lastname: Kessler
authors.affiliation: Division of Bioinformatics, Biocenter, Medical University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Michaela
authors.initials: M
authors.lastname: Willi
authors.affiliation: Division of Genomics and RNomics, Biocenter, Medical University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Ronald
authors.initials: R
authors.lastname: Gstir
authors.affiliation: Division of Bioinformatics, Biocenter, Medical University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Anne
authors.initials: A
authors.lastname: Krogsdam
authors.affiliation: Division of Molecular Biology, Biocenter, Medical University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Lusser
authors.affiliation: Department of Neurology, Medical University of Innsbruck, Anichstr. 35, 6020 Innsbruck, Austria.
authors.forename: Werner
authors.initials: W
authors.lastname: Poewe
authors.affiliation: Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, Innrain 66/G2, 6020 Innsbruck, Austria.
authors.forename: Gregor K
authors.initials: GK
authors.lastname: Wenning
authors.affiliation: Division of Genomics and RNomics, Biocenter, Medical University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hüttenhofer
authors.affiliation: Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, Innrain 66/G2, 6020 Innsbruck, Austria.
authors.forename: Nadia
authors.initials: N
authors.lastname: Stefanova
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D019578:Multiple System Atrophy / Q000235:genetics / Q000378:metabolism*; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger; D051844:alpha-Synuclein