RAS/MAPK overactivation drives motor axon loss in flies
An unbiased genetic screen in Drosophila revealed that excessive RAS/MAPK signaling causes adult-onset neurodegeneration that a MEK inhibitor rescues in a dose-dependent manner.
In fruit flies (Drosophila), researchers conducted an unbiased forward genetic mosaic screen to identify genes required to maintain adult motor axons and neuromuscular junctions. The screen revealed 49 mutations in 30 genes, including eight that cause adult-onset progressive degeneration. Loss of pebbled, the fly ortholog of mammalian RREB1, triggered adult-onset motor axonal and neuromuscular junction degeneration alongside age-dependent motor deficits. The gene encodes a zinc-finger transcription factor that negatively regulates RAS/MAPK target genes. Its loss, as well as the loss of other negative regulators, caused RAS/MAPK overactivation and motor decline. Treating adult mutant flies with the MEK1/2 inhibitor mirdametinib produced a dose-dependent rescue of the neurodegenerative phenotypes.
Why it matters
Axonal and synaptic degeneration are key hallmarks of age-related neurodegenerative diseases. Uncovering that excessive RAS/MAPK signaling triggers adult-onset degeneration highlights this pathway as a candidate mechanism and potential target for preserving motor function.
Caveats
The findings are limited to invertebrate models, and researchers have yet to confirm whether these mechanisms and drug responses translate to mammalian motor systems.
The paper
Excessive activation of the RAS/MAPK pathway triggers adult-onset motor axonal degeneration
Been M, Lambert E, Serna A et al.
iScience · 21 Sep 2026
