Altered microRNA expression profile in amyotrophic lateral sclerosis: a role in the regulation of NFL mRNA levels

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.

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

“…Defects in miRNA biogenesis, for example via knockout of Dicer, has been correlated with decreased motor activity and survival, muscle atrophy, denervation, spinal cord sclerosis, and axonopathy in mice [113]. Additionally, previous studies have demonstrated decreased miRNA expression in the ventral lumbar spinal cord from patients with ALS [114], and also in spinal MN with ALS-causing mutations [115]. These results highlight the potential utility of miRNAs as biomarkers for ALS.…”

Neuron-Microglia Interactions in Motor Neuron Degeneration. The Inflammatory Hypothesis in Amyotrophic Lateral Sclerosis Revisited

“…Changes in miRNA expression have been found in patients and the SOD1 G93A mouse [176,212,213] reflecting a dysfunction of the expressed RNA binding proteins involved in ALS. miRNAs are stable in cerebrospinal fluid, serum and other body fluids as exosomal cargos [214] and their concentrations are also modified in ALS [215] suggesting that the dysfunction of RNA binding proteins in ALS is systemic.…”

Causes and Consequences of MicroRNA Dysregulation in Neurodegenerative Diseases

“…MiR-146a is dysregulated in ALS [109]. The genome of miR146a is situated at 5q34, comprising a CpG island-enriched promoter.…”