Excessive activation of the RAS/MAPK pathway triggers adult-onset motor axonal degeneration

Axonal and synaptic degeneration are key hallmarks of neurodegenerative diseases, but the molecular mechanisms remain incompletely understood. Here, we performed an unbiased forward genetic mosaic screen in Drosophila to identify genes required for maintenance of adult motor axons and neuromuscular junctions (NMJs). We identified 49 mutations in 30 genes, including 8 causing adult-onset progressive degeneration. Loss of pebbled ( peb ), the Drosophila RAS- responsive element binding protein 1 ( RREB1 ) ortholog, causes adult-onset motor axonal and NMJ degeneration and age-dependent motor deficits. peb encodes a C 2 H 2 zinc-finger transcription factor that negatively regulates transcription of RAS/MAPK pathway target genes, and its loss resulted in RAS/MAPK pathway overactivation. Loss of other RAS/MAPK pathway negative regulators also induced adult-onset progressive NMJ degeneration and motor deficits. Importantly, treatment of adult flies with the MEK1/2 inhibitor mirdametinib induced a dosage-dependent rescue of peb mutant motor neurodegenerative phenotypes. Thus, RAS/MAPK pathway overactivation triggers adult-onset progressive neurodegeneration, which can be prevented by RAS/MAPK pathway inhibition.

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Journal
iScience
Published
2026-09-21
DOI
https://doi.org/10.1016/j.isci.2026.117507
Primary Topic
Amyotrophic Lateral Sclerosis Research
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article
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article

Excessive activation of the RAS/MAPK pathway triggers adult-onset motor axonal degeneration

Annette Schenck, Christian Gilissen, Patrik Verstreken, Céline Sijlmans et al.
iScience
Amyotrophic Lateral Sclerosis Research
article

Excessive activation of the RAS/MAPK pathway triggers adult-onset motor axonal degeneration

Annette Schenck, Christian Gilissen, Patrik Verstreken, Céline Sijlmans, Erwan Lambert, Marije Been, Boyd van Reijmersdal, Danique Beijer, Erik Storkebaum, Anouk C. G. Balvert, Pascal van Lith, Simon Heisinger, Sharon Gloudemans, Paulina Paškevičiūtė, Merli Kreshpani, Ana Serna, Catherine te Dorsthorst-Maas, Jan Veldink, Kevin Kenna, Stephan Züchner, Galuh Astuti, Henar Rodríguez Arias
article en

Abstract

Axonal and synaptic degeneration are key hallmarks of neurodegenerative diseases, but the molecular mechanisms remain incompletely understood. Here, we performed an unbiased forward genetic mosaic screen in Drosophila to identify genes required for maintenance of adult motor axons and neuromuscular junctions (NMJs). We identified 49 mutations in 30 genes, including 8 causing adult-onset progressive degeneration. Loss of pebbled ( peb ), the Drosophila RAS- responsive element binding protein 1 ( RREB1 ) ortholog, causes adult-onset motor axonal and NMJ degeneration and age-dependent motor deficits. peb encodes a C 2 H 2 zinc-finger transcription factor that negatively regulates transcription of RAS/MAPK pathway target genes, and its loss resulted in RAS/MAPK pathway overactivation. Loss of other RAS/MAPK pathway negative regulators also induced adult-onset progressive NMJ degeneration and motor deficits. Importantly, treatment of adult flies with the MEK1/2 inhibitor mirdametinib induced a dosage-dependent rescue of peb mutant motor neurodegenerative phenotypes. Thus, RAS/MAPK pathway overactivation triggers adult-onset progressive neurodegeneration, which can be prevented by RAS/MAPK pathway inhibition.

iScienceVol. 29(10)
Allen Institute for Brain Science (US), University of Miami (US), Radboud University Nijmegen (NL), Radboud University Medical Center (NL), University Medical Center Utrecht (NL), Radboud Institute for Molecular Life Sciences (NL), Dr. John T. Macdonald Foundation (US), VIB-KU Leuven Center for Brain & Disease Research (BE), Donders Institute for Brain, Cognition and Behaviour (NL)
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