Sexual Divergence in Microtubule Function: The Novel Intranasal Microtubule Targeting SKIP Normalizes Axonal Transport and Enhances Memory

Activity-dependent neuroprotective protein (ADNP), essential for brain formation, is a frequent autism spectrum disorder (ASD)-mutated gene. ADNP associates with microtubule end binding proteins (EBs) through its SxIP motif, to regulate dendritic spine formation and brain plasticity. Here, we reveal SKIP, a novel 4 amino acid peptide representing an EB-binding site, as a replacement therapy in an outbred Adnp-deficient mouse model. We discovered, for the first time, axonal transport deficits in Adnp+/- mice (measured by manganese-enhanced magnetic resonance imaging), with significant male-female differences. Furthermore, the Adnp+/- mice exhibited impaired hippocampal expression of key ASD-linked genes including the serotonin transporter (Slc6a4), the calcium channel (VDCC) and the autophagy regulator, BECN1 (Beclin1), in a sex-dependent manner. RNA-seq evaluations corroborated, in part, immunohistochemical and functional results. Intranasal SKIP treatment normalized social memory in 8-9-month-old Adnp+/--treated mice to placebo-control levels, while protecting axonal transport and ameliorating changes in ASD-like gene expression. SKIP presents a novel lead compound for ASD drug development, a prevalent unmet medical need. Overall design: 8 different samples were used, all in biological triplicates except for one sample with duplicates. Samples include 1 month and 5 months mice hippocampus of males and females, wild-type and Adnp+\-.