Journal
SCIENCE
Volume 326, Issue 5959, Pages 1549-1554Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1181046
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Funding
- National Cancer Institute [U24 CA126608]
- Simmons Cancer Center
- Department of Radiology
- National Heart, Lung, and Blood Institute [T32HL007360]
- National Institute of Neurological Disorders and Stroke (NINDS) [1F32NS061464-01A1]
- National Institute on Aging
- NIH
- Donald W. Reynolds Center for Clinical Cardiovascular Research
- Leducq Foundation
- Robert A. Welch Foundation
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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.
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