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 C2H2 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.