Altered Levels of MicroRNA-9, -206, and -132 in Spinal Muscular Atrophy and Their Response to Antisense Oligonucleotide Therapy

Abstract

The identification of noninvasive biomarkers to monitor the disease progression in spinal muscular atrophy (SMA) is becoming increasingly important. MicroRNAs (miRNAs) regulate gene expression and are implicated in the pathogenesis of neuromuscular diseases, including motor neuron degeneration. In this study, we selectively characterized the expression of miR-9, miR-206, and miR-132 in spinal cord, skeletal muscle, and serum from SMA transgenic mice, and in serum from SMA patients. A systematic analysis of miRNA expression was conducted in SMA mice with different disease severities (severe type I-like and mild type III-like) at different disease stages (pre-, mid-, and late-symptomatic stages), and in morpholino antisense oligonucleotide-treated mice. There was differential expression of all three miRNAs in spinal cord, skeletal muscle and serum samples in SMA mice. Serum miRNAs were altered prior to the changes in spinal cord and skeletal muscle at the presymptomatic stage. The altered miR-132 levels in spinal cord, muscle, and serum transiently reversed to normal level after a single-dose morpholino antisense oligomer PMO25 treatment in SMA mice. We also confirmed a significant alteration of miR-9 and miR-132 level in serum samples from SMA patients. Our study indicates the potential of developing miRNAs as noninvasive biomarkers in SMA.

miRNA in spinal muscular atrophy pathogenesis and therapy

“…Catapano et al . , in line with the previous work of Haramati et al . , demonstrated a significant down‐regulation of miR‐9 in the spinal cord of SMA I mice compared with controls.…”

“…Treatment with oligonucleotides to increase SMN does not significantly modify miRNA‐206 levels in SMA I mice, either in the spinal cord or in skeletal muscle, but does normalize its serum levels .…”

“…Catapano et al . showed a reduction of miR‐132 levels in the spinal cord of SMA I mice, which was reversible with morpholino therapy. miR‐132 levels in muscle were normal, while serum levels were elevated; these normalized after oligonucleotide therapy.…”

Diverse role of survival motor neuron protein

“…SMN may also have an indirect role in translation repression through the RNA interference pathway, since several microRNAs, including miR-9, miR-183, miR-206, miR-132 and miR-431 are aberrantly expressed in SMA [201–205]. Some of these microRNAs have been suggested to be potential targets for SMA therapy [204,205]. …”

MicroRNA regulators of cholinergic signaling link neuromuscular, cardiac and metabolic systems

“…Also, increases in the levels of miR-132, a known regulator of Acetylcholinesterase (AChE), potentiate ACh signaling in brain and body alike (34,35). MiR-132 has further been proposed as a biomarker for the moto-neuron disease spinal muscular atrophy (SMA), showing significantly higher levels in patients as opposed to controls (36). Thus, several known miRs play significant roles in various events along the life span of motor neurons, NMJs and muscles across multiple organisms, such as development, differentiation, functional maintenance, and regeneration after injury.…”