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bioRxiv · 10.1101/2025.03.12.642908

Modulation of autism-associated serotonin transporters by palmitoylation: Insights into the molecular pathogenesis and targeted therapies for autism spectrum disorder

Brown, C. R.·Foster, J. D.
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Abstract

BackgroundAutism spectrum disorder (ASD) is a developmental disorder of the nervous system characterized by a deficiency in interpersonal communication skills, a pathologic tendency for repetitive behaviors, and highly restrictive interests. The spectrum is a gradient-based construct used to categorize the widely varying degrees of ASD phenotypes, and has been linked to a genetic etiology in 25% of cases. Prior studies have revealed that 30% of ASD patients exhibit hyperserotonemia, or elevated whole blood serotonin, implicating the serotonergic system in the pathogenesis of ASD. Likewise, escitalopram, a selective-serotonin reuptake inhibitor (SSRI), has been demonstrated to improve aberrant behavior and irritability in ASD patients, potentially by modulating abnormal brain activation. Prior studies have uncovered proband patients with rare mutations in the human serotonin transporter (hSERT) that manifest enhanced surface expression and transport capacity, suggesting that abnormal enhancement of hSERT function may be involved in the pathogenesis of ASD. MethodsHEK-293 cells stably expressing WT, C109A, I425L, F465L, L550V, or K605N hSERT were subject to analysis for palmitoylation via Acyl-Biotin Exchange followed with hSERT immunoblotting. F465L functional enhancement was confirmed by surface analysis via biotinylation and saturation analysis via 5HT transport. F465L palmitoylation, surface expression and transport capacity were then assessed following treatment with 2-bromopalmitate or escitalopram. ResultsHere, we reveal that palmitoylation is enhanced in the ASD hSERT F465L and L550V coding variants, and confirm prior reports of enhanced kinetic activity and surface expression of F465L. Subsequently, treatment of F465L with the irreversible palmitoyl acyl-transferase inhibitor, 2-bromopalmitate (2BP), or escitalopram, rectified enhanced F465L palmitoylation, surface expression, and transport capacity to basal WT levels. LimitationsTests assessing L550V for surface expression, transport capacity, and reactivity to inhibition of palmitoylation was not assessed. In addition, further characterization is necessary for internalization rates, degradative mechanisms, the impact of cysteine-mediated substitutions, and other SSRIs on these processes. ConclusionsOverall, our results implicate disordered hSERT palmitoylation in the pathogenesis of serotonergic ASD subtypes, with basal recovery of these processes following escitalopram providing insight into its molecular utility as an ASD therapeutic.

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Brown, C. R., Foster, J. D.. 2025-03-13. Modulation of autism-associated serotonin transporters by palmitoylation: Insights into the molecular pathogenesis and targeted therapies for autism spectrum disorder. https://doi.org/10.1101/2025.03.12.642908

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