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.

Serum microRNA expression profiling in patients with multiple system atrophy

“…These differing results may be due to the differences between the brain tissue and serum samples used in each study. A previous study demonstrated that the expression of several miRNAs was altered in a mouse model of pre-motor stage MSA (17) however, in the present study, this altered expression of miRNA was not observed. These differing results may be due to differences between mouse brain tissue and human serum.…”

Role of microRNAs in the Regulation of α-Synuclein Expression: A Systematic Review

“…In total, six studies report in vivo overexpressing α-synuclein models to investigate the impact of α-synuclein in miRNA expression (Figure 5; Table 2 and Supplementary Table 3; Gillardon et al, 2008; Asikainen et al, 2010; Ubhi et al, 2014; Kong et al, 2015; Schafferer et al, 2016; Thome et al, 2016). Four out of six studies used mice models (Gillardon et al, 2008; Ubhi et al, 2014; Schafferer et al, 2016; Thome et al, 2016), one was performed in Caenorhabditis elegans (Asikainen et al, 2010) and one in a Drosophila model (Kong et al, 2015).…”

“…Four out of six studies used mice models (Gillardon et al, 2008; Ubhi et al, 2014; Schafferer et al, 2016; Thome et al, 2016), one was performed in Caenorhabditis elegans (Asikainen et al, 2010) and one in a Drosophila model (Kong et al, 2015). In all the species, overexpression of α-synuclein dysregulated several miRNAs (results summarized in Figure 5 and Supplementary Table 3).…”

“…The study of 266 unique mature mouse miRNA probes using μParaflo microfluidic chip (#MRA-1002) revealed that five microRNAs were downregulated in early-symptomatic α-synuclein (A30P)-transgenic mice: mmu-miR-10b, mmu-miR-10a, mmu-miR-212, mmu-miR-132 and mmu-miR-495. Two out of three mice studies were focused on MSA mice models overexpressing α-synuclein in oligodendroglial cells (Ubhi et al, 2014; Schafferer et al, 2016). Of these two MSA models, one was a comparative study of frontal cortex from several neurodegenerative transgenic mice models: (i) two different models of MSA in which α-synuclein was expressed under the control of oligodendrocyte-specific MPG promoter (lines MBP1- hαsyn and MBP29-hαsyn, medium and high αsyn expression respectively); (ii) DLB/PD; (iii) AD; and (iv) tauopathy (Ubhi et al, 2014).…”

“…promoter did not show significant differences. The second MSA study analyzed the striatum and SN in premotor MSA models overexpressing oligodendroglial α-synuclein in the third postnatal month using microarrays (Schafferer et al, 2016). The results showed that 33 miRNAs were dysregulated in the striatum and 59 miRNAs in the SN compared to control groups.…”