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

By Andrew H. Williams, Gregorio Valdez, V. Moresi, X. Qi, John R. McAnally, J. Elliott, R. Bassel-Duby, J. Sanes, E. Olson. Science, 2009

753 citations recorded by the source corpus.

An Innervative Small RNA Amyotrophic lateral sclerosis (ALS) is a relentless disease characterized by progressive degeneration of motor neurons that control muscle movement, leading to muscle atrophy and paralysis. Williams et al. (p. 1549; see the Perspective by Brown) show that a small noncoding RNA that is selectively expressed in skeletal muscle, miR-206, senses motor neuron injury or loss and helps ameliorate resultant muscle damage by promoting regeneration of neuromuscular synapses. Expression of miR-206 was dramatically induced in a mouse model of ALS, and when this RNA was removed from mice by genetic manipulation, the disease progressed at a faster rate. The salutary effects of miR-206 appear to be mediated through a signaling pathway in muscle cells involving histone deacetylase 4 and a fibro-blast growth factor modulator, activation of which leads to release of factors that promote nerve-muscle interactions. A small noncoding RNA promotes nerve-muscle interactions in response to motor neuron injury and slows disease progression. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by 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 that are 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 probably 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 the compensatory regeneration of neuromuscular synapses.

Subfields: Developmental Neuroscience, Genetics, Neurology

View Paper: https://www.semanticscholar.org/paper/4f7cc877d1257fe4f4a010b3da5d47edaf5ed48b

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Citations in the corpus

• Metazoan MicroRNAs (2018, background): “…of muscle and neuromuscular junctions after injury; accelerated pathology in neuromuscular disease models (ALS, Duchenne muscular dystrophy) (Williams et al., 2009; Liu et al., 2012) miR-7 (3) miR-7a-2 Male and female infertility with hypogonadism due to pituitary defect (Ahmed et al.,…”
• MicroRNAs and complex diseases: from experimental results to computational models (2019, neutral): “For example, mir-206 could slow down the progression of amyotrophic lateral sclerosis by sensing motor neuron injury [109].”
• microRNA-1 and microRNA-206 regulate skeletal muscle satellite cell proliferation and differentiation by repressing Pax7 (2010, background): “We and others previously demonstrated that miR-1 and miR-206 promote skeletal muscle terminal differentiation (Chen et al., 2006; Kim et al., 2006; Rosenberg et al., 2006; Williams et al., 2009).”
• A Long Noncoding RNA Controls Muscle Differentiation by Functioning as a Competing Endogenous RNA (2011, positive): “According to this classification, muscle specific pre-miR-206 and pre-miR-133b were annotated as overlapping with a noncoding RNA (Williams et al., 2009).”
• MicroRNAs in development and disease. (2011, background): “Moreover, like miR-1 and miR-133, ablation of miR-206 in a mouse model had no effect on normal muscle development (663).”