Sexual divergence in microtubule function: the novel intranasal microtubule targeting SKIP normalizes axonal transport and enhances memory

Mol Psychiatry. 2016 Oct;21(10):1467-76. doi: 10.1038/mp.2015.208. Epub 2016 Jan 19.


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 four-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. RNA sequencing evaluations showed major age, sex and genotype differences. Function enrichment and focus on major gene expression changes further implicated channel/transporter function and the cytoskeleton. In particular, a significant maturation change (1 month-five months) was observed in beta1 tubulin (Tubb1) mRNA, only in Adnp(+/+) males, and sex-dependent increase in calcium channel mRNA (Cacna1e) in Adnp(+/+) males compared with females. At the protein level, the Adnp(+/-) mice exhibited impaired hippocampal expression of the calcium channel (voltage-dependent calcium channel, Cacnb1) as well as other key ASD-linked genes including the serotonin transporter (Slc6a4), and the autophagy regulator, BECN1 (Beclin1), in a sex-dependent manner. Intranasal SKIP treatment normalized social memory in 8- to 9-month-old Adnp(+/-)-treated mice to placebo-control levels, while protecting axonal transport and ameliorating changes in ASD-like gene expression. The control, all d-amino analog D-SKIP, did not mimic SKIP activity. SKIP presents a novel prototype for potential ASD drug development, a prevalent unmet medical need.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Autism Spectrum Disorder / etiology
  • Autism Spectrum Disorder / genetics
  • Axonal Transport / genetics
  • Axonal Transport / physiology
  • Brain / metabolism
  • Calcium Channels / metabolism
  • Calcium Channels, R-Type / genetics
  • Calcium Channels, R-Type / metabolism
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism
  • Dendritic Spines / metabolism
  • Female
  • Hippocampus / metabolism
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism*
  • Male
  • Memory
  • Mice
  • Microtubules / metabolism
  • Microtubules / physiology*
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism*
  • RNA, Messenger / metabolism
  • Sex Factors
  • Tubulin / metabolism
  • Tubulin Modulators / metabolism


  • Adnp protein, mouse
  • Cacna1e protein, mouse
  • Calcium Channels
  • Calcium Channels, R-Type
  • Cation Transport Proteins
  • Homeodomain Proteins
  • Nerve Tissue Proteins
  • RNA, Messenger
  • Tubulin
  • Tubulin Modulators