MicroRNA-206 delays ALS progression and promotes regeneration of neuromuscular synapses in mice.
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.
Williams
Andrew H
AH
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Valdez
Gregorio
G
Moresi
Viviana
V
Qi
Xiaoxia
X
McAnally
John
J
Elliott
Jeffrey L
JL
Bassel-Duby
Rhonda
R
Sanes
Joshua R
JR
Olson
Eric N
EN
D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D001369:Axons / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009046:Motor Neurons / Q000473:pathology / Q000502:physiology*; D009121:Muscle Denervation; D018482:Muscle, Skeletal / Q000294:innervation / Q000378:metabolism* / Q000473:pathology; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism; D018008:Myogenin / Q000235:genetics / Q000378:metabolism; D009416:Nerve Regeneration; D009469:Neuromuscular Junction / Q000254:growth & development / Q000473:pathology* / Q000502:physiology*; D034622:RNA Interference; D015398:Signal Transduction; D015533:Transcriptional Activation; D015854:Up-Regulation
D002352:Carrier Proteins; C489453:Fgfbp1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D035683:MicroRNAs; C540669:Mirn206 microRNA, mouse; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D018008:Myogenin; D005346:Fibroblast Growth Factors; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases