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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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
Pages (from-to)1467-1476
Number of pages10
JournalMolecular Psychiatry
Volume21
Issue number10
DOIs
StatePublished - 1 Oct 2016

Funding

FundersFunder number
AMN Foundation
Adams family
Miriam and Sheldon G. Adelson Graduate School of Medicine, Sackler Faculty of Medicine, Tel Aviv University
Canadian Friends of Tel Aviv University
Ministry of Science, Technology and Space
Israel Science Foundation
Tel Aviv University

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