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.
Highlights
Multiple system atrophy (MSA) is a fatal, late onset, sporadic neurodegenerative disorder, which is characterized by a combination of non-motor and motor symptoms with rapid progression resulting in disability and death shortly after clinical diagnosis [1]
The motor and neuropathological analysis of the MSA transgenic mouse showed that, at the young age (PM3), the model replicates an early pre-motor phase of MSA-like pathology with presence of α-synuclein accumulation in oligodendrocytes but lack of neuronal loss in substantia nigra (SN) and striatum and respectively absence of motor deficits
The accumulation of human α-synuclein in oligodendrocytes triggers a yet undefined cascade of events that leads to neuronal loss in SN and later on in striatum, which results in motor deterioration [12]
Summary
Multiple system atrophy (MSA) is a fatal, late onset, sporadic neurodegenerative disorder, which is characterized by a combination of non-motor and motor symptoms with rapid progression resulting in disability and death shortly after clinical diagnosis [1]. The major hallmark of the disease is the widespread occurrence of α-synuclein positive cytoplasmic inclusions in oligodendrocytes called glial cytoplasmic inclusions (GCIs) [3,4,5]. It is currently accepted that α-synuclein plays a major role in the pathogenesis of MSA [6]. About the early events in the disease cascade before its clinical onset due to the difficulties to address this question in patients because early diagnostic markers for MSA are lacking at present
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