Axon degeneration and disruption of neuromuscular junctions (NMJs) are key events in amyotrophic lateral sclerosis (ALS) pathology. Although the disease’s etiology is not fully understood, it is thought to involve a non–cell-autonomous mechanism and alterations in RNA metabolism. Here, we identified reduced levels of miR126-5p in presymptomatic ALS male mice models, and an increase in its targets: axon destabilizing Type 3 Semaphorins and their coreceptor Neuropilins. Using compartmentalized in vitro cocultures, we demonstrated that myocytes expressing diverse ALS-causing mutations promote axon degeneration and NMJ dysfunction, which were inhibited by applying Neuropilin1 blocking antibody. Finally, overexpressing miR126-5p is sufficient to transiently rescue axon degeneration and NMJ disruption both in vitro and in vivo. Thus, we demonstrate a novel mechanism underlying ALS pathology, in which alterations in miR126-5p facilitate a non–cell-autonomous mechanism of motor neuron degeneration in ALS.
Bibliographical noteFunding Information:
ThisworkwassupportedbytheRosetreesTrust,AlfredTaubman,theIsrALSFoundation,IsraelScienceFounda-tion Grant 561-11, and European Research Council Grant 309377 to E.P., Israel Science Foundation Grant 947/14 to O.B.,andNationalInstitutesofHealthGrantRO1-NS44292toD.T.WethankDr.EranHorensteinformiR126andmiR 142,aswellasforextraSOD1G93Amice;Dr.MickeyHarlevandLiorBikovskiforassistingwithmouseinjectionandthe behavioral tests; and Konstantin Voloshin for help in NMJ analysis. The authors declare no competing financial interests. *R.M. and A.I. contributed equally to this work.
© 2018 the authors.
- Axon degeneration
- Microfluidic chambers