Abstract
BackgroundAmyotrophic Lateral Sclerosis (ALS) is a progressive, adult onset, fatal neurodegenerative disease of motor neurons. There is emerging evidence that alterations in RNA metabolism may be critical in the pathogenesis of ALS. MicroRNAs (miRNAs) are small non-coding RNAs that are key determinants of mRNA stability. Considering that miRNAs are increasingly being recognized as having a role in a variety of neurodegenerative diseases, we decided to characterize the miRNA expression profile in spinal cord (SC) tissue in sporadic ALS (sALS) and controls. Furthermore, we performed functional analysis to identify a group of dysregulated miRNAs that could be responsible for the selective suppression of low molecular weight neurofilament (NFL) mRNA observed in ALS.ResultsUsing TaqMan arrays we analyzed 664 miRNAs and found that a large number of miRNAs are differentially expressed in ventral lumbar SC in sALS compared to controls. We observed that the majority of dysregulated miRNAs are down-regulated in sALS SC tissues. Ingenuity Pathway Analysis (IPA) showed that dysregulated miRNAs are linked with nervous system function and cell death. We used two prediction algorithms to develop a panel of miRNAs that have recognition elements within the human NFL mRNA 3′UTR, and then we performed functional analysis for these miRNAs. Our results demonstrate that three miRNAs that are dysregulated in sALS (miR-146a*, miR-524-5p and miR-582-3p) are capable of interacting with NFL mRNA 3′UTR in a manner that is consistent with the suppressed steady state mRNA levels observed in spinal motor neurons in ALS.ConclusionsThe miRNA expression profile is broadly altered in the SC in sALS. Amongst these is a group of dysregulated miRNAs directly regulate the NFL mRNA 3′UTR, suggesting a role in the selective suppression of NFL mRNA in the ALS spinal motor neuron neurofilamentous aggregate formation.
Highlights
Amyotrophic Lateral Sclerosis (ALS) is a progressive, adult onset, fatal neurodegenerative disease of motor neurons
To elucidate whether the group of functional miRNAs were acting on NFL mRNA stability or translational regulation, we studied changes on the luciferase mRNA levels caused by NFL 3′30 untranslated region (UTR) regulation through miRNAs
Amongst those miRNAs that we observed to be differentially expressed in ventral lumbar spinal cord (SC) in sporadic ALS (sALS) compared to controls, we identified a panel of miRNAs with miRNA recognition element (MRE) in the human NFL mRNA 3′UTR that were able to regulate the expression of a luciferase reporter bearing this 3′UTR in mammalian cells
Summary
Amyotrophic Lateral Sclerosis (ALS) is a progressive, adult onset, fatal neurodegenerative disease of motor neurons. While the net effect of the coordinated action of these RNA binding proteins on NFL mRNA stability in vivo remains to be clarified, it is of interest that both NFL mRNA and TDP-43 are differentially partitioned to degradative granules (P-bodies) in ALS affected lumbar spinal motor neurons [12]. This is in contrast to the physiological partitioning of TDP-43 to stress granules observed following axonal injury [19,20]. Both stress granules and P-bodies exist in a constant state of dynamic flux, mediated by the nature of associated microRNAs miRNAs; [21,22]
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