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 underlying molecular mechanisms are incompletely understood. Here, we performed an unbiased forward genetic mosaic screen to identify genes required for maintenance of adult motor axons and neuromuscular junctions (NMJs) in the Drosophila leg. We identified 49 mutations in 30 genes, including mutations in 8 genes resulting in adult-onset progressive degeneration. We found that loss of pebbled ( peb ) function results in adult-onset motor axonal and NMJ degeneration, and age-dependent motor deficits. Peb is the Drosophila RREB1 ortholog, a C ₂ H ₂ zinc-finger transcription factor that negatively regulates transcription of RAS/MAPK pathway target genes. Loss of peb function resulted in excessive RAS/MAPK pathway activation, and loss of function of other negative regulators of the RAS/MAPK pathway 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 results in adult-onset progressive neurodegeneration, which can be prevented by RAS/MAPK pathway inhibition.