Muscle microRNA signatures as biomarkers of disease progression in amyotrophic lateral sclerosis

Abstract

ALS is a fatal neurodegenerative disorder of motor neurons leading to progressive atrophy and weakness of muscles. Some of the earliest pathophysiological changes occur at the level of skeletal muscle and the neuromuscular junction. We previously identified distinct mRNA patterns, including members of the Smad and TGF-β family, that emerge in muscle tissue at the earliest (pre-clinical) stages. These patterns track disease progression in the mutant SOD1 mouse and are present in human ALS muscle. Because miRNAs play a direct regulatory role in mRNA expression, we hypothesized in this study that there would be distinct miRNA patterns in ALS muscle appearing in early stages that could track disease progression. We performed next-generation miRNA sequencing on muscle samples from G93A SOD1 mice at early (pre-clinical) and late (symptomatic) stages, and identified distinct miRNA patterns at both stages with some overlap. An Ingenuity Pathway Analysis predicted effects on a number of pathways relevant to ALS including TGF-β signaling, axon guidance signaling, and mitochondrial function. A subset of miRNAs was validated in the G93A SOD1 mouse at four stages of disease, and several appeared to track disease progression, including miR-206. We assessed these miRNAs in a large cohort of human ALS and disease control samples and found that some had similar changes but were not specific for ALS. Surprisingly, miR-206 levels did not change overall compared to normal controls, but did correlate with changes in strength of the muscle biopsied. In summary, we identified distinct miRNA patterns in ALS muscle that reflected disease stage which could potentially be used as biomarkers of disease activity.

MicroRNAs as Biomarkers in Amyotrophic Lateral Sclerosis

“…At the same time, a significant reduction of this miRNA was present in a specific ALS patients’ group with higher disease severity [ 95 ], suggesting changes in its expression during the disease progression. In contrast, however, other studies detected a down-regulation of miR-133a in human biopsies, as reported also in mice [ 92 , 94 ]. At the moment, the strongest data are those concerning miR-206.…”

“…Most studies focused on the expression of myo-miRNAs [ 90 , 91 , 92 , 93 ]; only in some cases also other miRNAs were included, for example miRNAs related to inflammation/angiogenesis [ 93 ] or selected by microarray [ 72 ] or NGS approaches [ 94 , 95 ]. Overall, results are sometimes contrasting and poorly reproducible.…”

“…Moreover, the authors reported a significant inverse correlation between this miRNA and the muscle power of the biopsied muscle, hypothesizing that it could be a marker of disease activity. This finding highlights the importance to associate miR-206 levels with muscle-specific clinical assessment rather than overall clinical status [ 94 ].…”

Regional difference in microRNA regulation in the skull vault

“…In our study, we further revealed another feature in the frontal and parietal bone with a distinct miRNA pattern. Small RNA sequencing has been demonstrated to be effective to identify novel miRNAs, and based on this technique, we found that 83 known miRNAs were significantly expressed in frontal versus parietal bone, and about 29 potential novel miRNAs candidates at 18 to 26 nt in length were found. These novel miRNAs are worthy for further functions analysis in osteogenic capacities in Fb versus Pb.…”

Effect of Regulatory Network of Exosomes and microRNAs on Neurodegenerative Diseases

“…[ 5 ] MiRNAs regulate the level of proteins by regulating levels of mRNAs. [ 16 ] Alterations in the expression profile of miRNAs in Alzheimer's disease (AD) patients,[ 17 ] Parkinson's disease (PD) patients,[ 18 ] amyotrophic lateral sclerosis (ALS) patients,[ 19 ] and Huntington's disease (HD) prodromal patients[ 20 ] illustrate the important role of miRNAs in neurodegenerative diseases. Dysregulation of miRNAs is closely related with AD, PD, HD, and ALS.…”