MicroRNA-206 Delays ALS Progression and Promotes Regeneration of Neuromuscular Synapses in Mice

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, resulting in loss of motor neurons, denervation of target muscles, muscle atrophy and paralysis. Understanding ALS pathogenesis may require a fuller understanding of the bidirectional signaling between motor neurons and skeletal muscle fibers at neuromuscular synapses. Here we show that a key regulator of this signaling is miR-206, a skeletal muscle-specific microRNA that is dramatically induced in a mouse model of ALS. Mice genetically deficient in miR-206 form normal neuromuscular synapses during development, but deficiency of miR-206 in the ALS mouse model accelerates disease progression. MiR-206 is required for efficient regeneration of neuromuscular synapses after acute nerve injury, which likely accounts for its salutary effects in ALS. MiR-206 mediates these effects, at least in part, through histone deacetylase 4 and fibroblast growth factor signaling pathways. Thus, miR-206 slows ALS progression by sensing motor neuron injury and promoting compensatory regeneration of neuromuscular synapses.Amyotrophic lateral sclerosis (ALS) is the most common adult motor neuron disease (1). Symptoms of the disease include atrophy and paralysis of lower limb and respiratory muscles due to degeneration of motor neurons. There is currently no effective treatment. Thus, identification of the signaling pathways and cellular mediators of ALS remains a major challenge in the search for novel therapeutics (2).In light of recent studies implicating microRNAs (miRNAs) in stress responses in muscle (3), we investigated whether disease progression in a mouse model of ALS was accompanied

Age‐related changes in miR‐143‐3p:Igfbp5 interactions affect muscle regeneration

“…This is keeping with previous data showing that such compensatory mechanisms exist. For example, increased expression of miR‐206 in the muscle of ALS mouse model has been shown to compensate the neuromuscular interactions (Williams et al ., 2009). …”

αCAR IGF‐1 vector targeting of motor neurons ameliorates disease progression in ALS mice

“…Combinatorial gene therapy utilizing multicistronic LV vectors expressing additional factors, such as heat shock proteins49 or miR‐206,50 could further enhance the potency of this approach. As the aCAR antibody expressed on the LV surface binds both mouse and human receptors51 testing in iPSC‐derived motor neurons from ALS52 patients could be possible and might enhance translatability.…”

A Novel Enhancer of the Wound Healing Process

“…Indeed, these FGFs were identified as interaction partners of FGF-BP1, and the latter was shown to promote the activity of low concentrations of FGF7 and FGF10. 17,18 Therefore, it seems likely that activation of FGF-BP1 expression in keratinocytes of healing wounds promotes re-epithelialization. In addition, FGF-BP1 may also act on cells of the granulation tissue (eg, endothelial cells), because it is a secreted protein and is also expressed in cells of the dermis and granulation tissue.…”

“…This hypothesis is further supported by the observation that FGF-BP down-regulation was associated with the failure to re-innervate the muscles during the progression of amyotrophic lateral sclerosis. 18 Thus, FGF-BP1 may well emerge as a global player in tissue repair processes with an as yet underestimated therapeutic potential.…”