Loss of spermine synthase recapitulates RAS/MAPK and sensory processing phenotypes of Drosophila RASopathy models

Hyperactivation of RAS/MAPK signaling is a hallmark of RASopathies, genetic developmental conditions associated with cognitive and sensory processing impairments. Genes linked to this pathway have been reported to be enriched among Drosophila models with habituation deficits, a behavioral phenotype reflecting impaired sensory filtering. To investigate whether RAS/MAPK overactivation extends beyond classical RASopathies, we generated 89 and screened 41 viable habituation deficient Drosophila RNAi models, measuring pathway activity as an increased phosphorylated ERK to ERK ratio. This screen identified Sms, the ortholog of human spermine synthase (SMS), implicated in Snyder-Robinson syndrome. RAS/MAPK overactivation along with hyperreactivity and habituation impairments were confirmed in a full loss-of-function mutant. An RNAi screen targeting polyamine pathway genes identified Sat (human SAT1/2, SATL1), with independent models reproducing aspects of these phenotypes. Knockdown of Sms or Sat in GABAergic neurons impaired habituation, suggesting a role for polyamine metabolism in inhibitory circuit function. These findings reveal previously unrecognized convergence between polyamine dysregulation and RASopathies, raising the possibility for shared therapeutic opportunities through modulation of either pathway.