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

N. Amram, G. Hacohen-Kleiman, S. Sragovich, A. Malishkevich, J. Katz, O. Touloumi, R. Lagoudaki, N. C. Grigoriadis, E. Giladi, A. Yeheskel, M. Pasmanik-Chor, Y. Jouroukhin, I. Gozes

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1467-1476
Number of pages10
JournalMolecular psychiatry
Volume21
Issue number10
DOIs
StatePublished - Oct 1 2016
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Amram, N., Hacohen-Kleiman, G., Sragovich, S., Malishkevich, A., Katz, J., Touloumi, O., Lagoudaki, R., Grigoriadis, N. C., Giladi, E., Yeheskel, A., Pasmanik-Chor, M., Jouroukhin, Y., & Gozes, I. (2016). Sexual divergence in microtubule function: The novel intranasal microtubule targeting SKIP normalizes axonal transport and enhances memory. Molecular psychiatry, 21(10), 1467-1476. https://doi.org/10.1038/mp.2015.208