Dysregulation of protein translation and sensory function in <em>Drosophila melanogaster</em> autism models

Abstract

Autism spectrum disorders (ASDs) are highly heterogeneous neurodevelopmental conditions affecting 1–2% of children and characterized by impaired social interaction, repetitive behaviors, and sensory abnormalities. Although a growing number of genetic risk factors for ASD have been uncovered, the molecular and cellular mechanisms underlying their pathogenic effects remain largely unclear. Increasing evidence indicates that dysregulated synaptic protein synthesis is a convergent driver of ASD pathology. <br/> In this study, I identified <em>Drosophila Tao</em>, the conserved ortholog of the ASD risk gene TAOK2, as a key regulator of neuronal translation and proteostasis. Loss of Tao enhances global protein synthesis, increases S6 kinase (S6k) mRNA translation and active phospho-S6K levels, indicating disrupted balance between protein production and degradation. Reducing S6k gene dosage partially rescued behavioral defects in <em>Tao</em>^+/− flies, supporting a functional connection between <em>Tao</em> and mTOR–S6K signaling. Restoring Tao function in somatosensory neurons with human TAOK2, but not an ASD-associated variant (TAOK2-A135P), rescued sensory and social behavioral deficits in <em>Tao</em>^+/− flies, highlighting conserved kinase-dependent functions and implicating peripheral sensory neurons as a mechanistic contributor to ASD-related behaviors. <br/> Given that TAOK2 is a direct translational target of FMRP, I further examined <em>Tao</em>–<em>Fmr1</em> interactions. Loss of Tao increases dFMRP levels and reduces synaptic protein translation. Transcriptomic analysis revealed substantial overlap between Tao-dependent translational targets, ASD risk genes, and FMRP-bound mRNAs. Together, these findings position Tao within a conserved translational network centered on different ASD genes, linking disrupted proteostasis and synaptic dysfunction to ASD-related behavioral phenotypes.