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An integrative miRNA-mRNA expression analysis identifies miRNA signatures associated with SOD1 and TARDBP
Banaja P Dash1, Axel Freischmidt2, Jochen H Weishaupt3
1Translational Neurodegeneration Section "Albrecht Kossel", Department of Neurology, University Medical Center Rostock, Gehlsheimer Str. 20, Rostock 18147, Germany.
Abstract:
MicroRNAs (miRNAs) are a subset of small non-coding single-stranded RNA molecules involved in the regulation of post-transcriptional gene expression of a variety of transcript targets. Therefore altered miRNA expression may result in the dysregulation of key genes and biological pathways that has been reported with the onset and progression of neurodegenerative diseases, such as Amyotrophic lateral sclerosis (ALS). ALS is marked by a progressive degeneration of motor neurons (MNs) present in the spinal cord, brain stem and motor cortex. Although the pathomechanism underlying molecular interactions of ALS remains poorly understood, alterations in RNA metabolism, including dysregulation of miRNA expression in familial as well as sporadic forms are still scarcely studied. In this study, we performed combined transcriptomic data and miRNA profiling in MN samples of the same samples of iPSC-derived MNs from SOD1- and TARDBP (TDP-43 protein)-mutant-ALS patients and healthy controls. We report a global upregulation of mature miRNAs, and suggest that differentially expressed (DE) miRNAs have a significant impact on mRNA-level in SOD1-, but not in TARDBP-linked ALS. Furthermore, in SOD1-ALS we identified dysregulated miRNAs such as miR-124-3p, miR-19b-3p and miR-218 and their potential targets previously implicated in important functional process and pathogenic pathways underlying ALS. These miRNAs may play key roles in the neuronal development and cell survival related functions in SOD1-ALS. Altogether, we provide evidence of miRNA regulated genes expression mainly in SOD1 rather than TDP43-ALS.
Insights
Altered microRNA (miRNA) expression impacts gene regulation in Amyotrophic Lateral Sclerosis (ALS). This study found global miRNA upregulation in SOD1-ALS, affecting mRNA levels and identifying specific miRNAs involved in neuronal function.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- MicroRNAs (miRNAs) are key regulators of gene expression.
- Dysregulated miRNA expression is implicated in neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS).
- Understanding miRNA roles in ALS pathogenesis, particularly in SOD1 and TDP-43 linked forms, is crucial.
Purpose of the Study:
- To investigate miRNA expression profiles in induced pluripotent stem cell (iPSC)-derived motor neurons (MNs) from ALS patients.
- To compare miRNA dysregulation in SOD1-mutant ALS versus TARDBP (TDP-43)-mutant ALS.
- To identify specific miRNAs and their targets impacting ALS pathology.
Main Methods:
- Combined transcriptomic and miRNA profiling of iPSC-derived MNs.
- Analysis of samples from SOD1-mutant ALS, TARDBP-mutant ALS, and healthy controls.
- Identification of differentially expressed (DE) miRNAs and their predicted mRNA targets.
Main Results:
- Global upregulation of mature miRNAs observed in ALS motor neurons.
- DE miRNAs significantly impacted mRNA levels in SOD1-ALS, but not in TARDBP-ALS.
- Specific miRNAs (miR-124-3p, miR-19b-3p, miR-218) and their targets implicated in SOD1-ALS pathogenesis were identified.
Conclusions:
- miRNA dysregulation plays a significant role in SOD1-linked ALS, affecting gene expression and neuronal function.
- The identified miRNAs may be critical in neuronal development and survival pathways in SOD1-ALS.
- Evidence suggests distinct miRNA regulatory mechanisms in SOD1-ALS compared to TDP-43-ALS.
