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, researchers from the University of Texas Southwestern Medical Center 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.

miR-206 targets HDAC4

(A) Luciferase activity of COS1 cells co-transfected with WT or mutant HDAC4 3’UTR-luciferase constructs with a miR-206 expression plasmid. (B) Quantitation of HDAC4 protein expression in muscle lysates isolated from wild-type (WT) and miR-206^−/− (miR-206 KO) mice following 3 weeks of denervation. *p < 0.02 by t test. n=3. (C) Immunohistochemistry shows an increase in reinnervation in HDAC4 mKO mutant mice compared to WT mice 7 days following nerve crush. Scale bar=10 µm. (D) Number of reinnervated NMJs in WT and HDAC4 mKO mice following sciatic nerve crush for 7 days. *p < 0.05 by t test. n=3–8. (E) Postsynaptic area occupied by the reinnervating nerve (in %) 7 days after crushing the sciatic nerve in WT and HDAC4 mKO mice. *p < 0.02. (F) Decrease in expression of Fgfbp1 transcripts in miR-206^−/− (KO) muscles 3 weeks after nerve transection. *p < 0.02 by t test. n=3–5. (G) Increase in expression of Fgfbp1 transcripts in HDAC4 mKO muscles 7 days after nerve crush. *p < 0.0005 by t test. n=3–5. (H) Immunohistochemistry shows an inhibition of synaptic-vesicle clustering in neonatal NMJs upon knock-down of FGFBP1. Scale bar= 10 µm. (I) NMJ size in muscle fibers expressing LacZ or FGFBP1 shRNAs. Mice were electroporated at P0 and analyzed at P8. *p < 0.02 by t test. n=4. Values represent means ± SEM (J) Schematic of miR-206 up-regulation and function after denervation. (K) Mechanism of miR-206-dependent reinnervation.

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Reference

Elliott JL, McAnally J, Moresi V, Olson EN, Qi X, Sanes JR, Valdez G, Williams AH. (2009) MicroRNA-206 delays ALS progression and promotes regeneration of neuromuscular synapses in mice. Science 326(5959), 1549-54. [article]