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