Mir126-5p downregulation facilitates axon degeneration and nmj disruption via a non–cell-autonomous mechanism in ALS

Roy Maimon, Ariel Ionescu, Avichai Bonnie, Sahar Sweetat, Shane Wald-Altman, Shani Inbar, Tal Gradus, Davide Trotti, Miguel Weil, Oded Behar, Eran Perlson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

34 Scopus citations


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.

Original languageAmerican English
Pages (from-to)5478-5494
Number of pages17
JournalJournal of Neuroscience
Issue number24
StatePublished - 13 Jun 2018

Bibliographical note

Funding 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.

Publisher Copyright:
© 2018 the authors.


  • ALS
  • Axon degeneration
  • MiRNA
  • Microfluidic chambers
  • NMJ
  • Sema3A


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