Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyotrophic Lateral Sclerosis / pathology
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Amyotrophic Lateral Sclerosis / physiopathology*
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Animals
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Axons / physiology
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Disease Models, Animal
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Disease Progression
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Fibroblast Growth Factors / metabolism
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Histone Deacetylases / genetics
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Histone Deacetylases / metabolism
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Intercellular Signaling Peptides and Proteins
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Intracellular Signaling Peptides and Proteins
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Mice
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Mice, Transgenic
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MicroRNAs / genetics
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MicroRNAs / metabolism*
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Motor Neurons / pathology
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Motor Neurons / physiology*
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Muscle Denervation
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Muscle, Skeletal / innervation
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Muscle, Skeletal / metabolism*
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Muscle, Skeletal / pathology
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MyoD Protein / genetics
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MyoD Protein / metabolism
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Myogenin / genetics
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Myogenin / metabolism
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Nerve Regeneration
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Neuromuscular Junction / growth & development
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Neuromuscular Junction / pathology*
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Neuromuscular Junction / physiology*
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RNA Interference
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Signal Transduction
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Transcriptional Activation
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Up-Regulation
Substances
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Carrier Proteins
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Fgfbp1 protein, mouse
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Intercellular Signaling Peptides and Proteins
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Intracellular Signaling Peptides and Proteins
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MicroRNAs
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Mirn206 microRNA, mouse
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MyoD Protein
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MyoD1 myogenic differentiation protein
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Myogenin
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Fibroblast Growth Factors
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Hdac5 protein, mouse
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Histone Deacetylases