Survival of motor neuron protein downregulates miR‐9 expression in patients with spinal muscular atrophy

Abstract

Spinal muscular atrophy (SMA) is a lethal hereditary disease caused by homozygous absence of the survival of the motor neuron (SMN) 1 gene (SMN1), and it is the leading genetic cause of infant mortality. The severity of SMA is directly correlated with SMN protein levels in affected patients; however, the cellular regulatory mechanisms for SMN protein expression are not completely understood. In this study, we investigated the regulatory effects between SMN expression and miR-9a, a downstream noncoding small RNA. Using an inducible SMN short hairpin RNA interference (shRNAi) system in NSC 34 and human skin fibroblast cells, cellular miR-9 levels and SMN protein repression were time-dependently upregulated. Conversely, cellular miR-9 levels decreased when HeLa cells were transfected with SMN protein fused with green fluorescent protein. In SMA-like mice spinal cords and human primary skin fibroblasts isolated from patients with different degrees of SMA, human SMN exhibited a disease severity-dependent decrease, whereas cellular miR-9 levels increased. These results clearly suggested that cellular SMN proteins regulated miR-9 expression and that miR-9 expression was related to SMA severity. Thus, miR-9 may be a marker for SMA prognosis.

Decreased microRNA levels lead to deleterious increases in neuronal M2 muscarinic receptors in Spinal Muscular Atrophy models

“…More studies will be needed to confirm that miR-2 and miR-128 are orthologs. Regardless, the results presented here, in conjunction with previous research, suggest that overall miRNA misregulation contributes to neuronal defects when SMN levels decrease (Haramati et al, 2010; Kye et al, 2014; Valsecchi et al, 2015; Wang et al, 2014; Wertz et al, 2016). …”

“…Disruption of the miRNA pathway in spinal MNs leads to severe degeneration (Haramati et al, 2010). SMN loss alters levels and/or activity of specific miRNAs (Haramati et al, 2010; Kye et al, 2014; Valsecchi et al, 2015; Wang et al, 2014), but the cellular mechanisms leading to altered miRNA expression and/or function are unknown. The RNA helicase Gemin3 associates with both SMN and RNA-induced silencing complex components (Charroux et al, 1999; Höck et al, 2007; Hutvágner and Zamore, 2002; Meister et al, 2005; Mourelatos et al, 2002; Murashov et al, 2007).…”

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

“…19 The conversely increased level of miR-9 in TA muscles is consistent with a report that miR-9 is upregulated in fibroblasts with SMN protein deficiency. 40 miR-132 also has contrary abundance in spinal cord and skeletal muscle. miR-132 plays an important role in neurite outgrowth.…”

MotomiRs: miRNAs in Motor Neuron Function and Disease

“…It was reported that mice lacking the miRNA-processing enzyme Dicer selectively in motor neurons display hallmarks of SMA (Haramati et al, 2010). Also, SMN protein has been shown to alter miRNA expression and distribution in neurons (Kye et al, 2014; Wang et al, 2014). Specifically, miR-183 is increased in neurites of SMN-deficient neurons.…”

“…SMN protein also down-regulates the expression of miR-9a. Interestingly, miR-9a levels have shown a positive correlation with SMA severity (Wang et al, 2014). A more recent study has shown that miR-431, involved in motor neuron neurite length, also plays a role in the SMA motor neuron phenotype.…”