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Science 326 (5959): 1549-1554

Copyright © 2009 by the American Association for the Advancement of Science

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

Andrew H. Williams,1,* Gregorio Valdez,2,* Viviana Moresi,1 Xiaoxia Qi,1 John McAnally,1 Jeffrey L. Elliott,3 Rhonda Bassel-Duby,1 Joshua R. Sanes,2 Eric N. Olson1,{dagger}

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.

1 Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
2 Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, MA 02138, USA.
3 Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: eric.olson{at}utsouthwestern.edu


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