miR126-5p Downregulation Facilitates Axon Degeneration and NMJ Disruption via a Non-Cell-Autonomous Mechanism in ALS

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
Roy MaimonEran Perlson

Abstract

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.SIGNIFICANCE STATEMENT Despite some progress, currently no effective treatment is available for amyotrophic lateral sclerosis (ALS). We suggest a novel regulatory role for miR126-5p in ALS and demonstrate, for the first time, a mechanis...Continue Reading

Citations

Oct 16, 2018·ELife·Éric MartineauRichard Robitaille
Jan 11, 2020·EMBO Reports·Jakub ZiakMartin Balastik
Jan 10, 2019·Frontiers in Bioengineering and Biotechnology·Maider Badiola-MateosJosep Samitier
Aug 7, 2019·Disease Models & Mechanisms·Martin CrivelloJochen H M Prehn
Jan 1, 2021·Journal of Neurochemistry·Rianne de JonghR Jeroen Pasterkamp
Feb 26, 2021·Biotechnology and Bioengineering·Ki-Young SongAna I Teixeira
Jul 3, 2021·International Journal of Molecular Sciences·Greta Limoni
Jul 28, 2021·Free Radical Biology & Medicine·J Jiménez-VillegasA I Rojo
Aug 7, 2021·Journal of Personalized Medicine·Oihane Pikatza-MenoioSonia Alonso-Martín
Dec 17, 2021·Frontiers in Neuroscience·Amélie Poulin-BrièreSilvia Pozzi
Jan 9, 2022·Molecular Neurobiology·Sagar VermaVibha Taneja

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Methods Mentioned

BETA
transgenic
PCR
biopsies
Protein Assay
FCS
Chip
transfection

Software Mentioned

Logica
CatWalk XT
Nanostring
RTCA
CatWalk
Andor IQ2
Patho

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