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

Molecular Psychiatry volume 21, pages 1467–1476 (2016)Cite this article

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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.

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Acknowledgements

Illana Gozes laboratory is supported by the AMN Foundation, the Israel Ministry of Science, Technology and Space, Israel Science Foundation, CFTAU Montreal Circle of Friends and the Adams family, Adams Super Center for Brain Studies, the Edersheim Levie-Gitter Institute for Functional Brain Imaging, the Diana and Zelman Elton (Elbaum) Laboratory for Molecular Neuroendocrinology and the Lily and Avraham Gildor Chair for the Investigation of Growth Factors at Tel Aviv University. Illana Gozes is a Humboldt Award Recipient and was a fellow at the Hanse-Wissenschftenkolleg, Germany. This study is in partial fulfillment graduate studies requirements for Noy Amram, Gal Hacohen Kleiman, Anna Malishkevich, Jeny Katz and Shlomo Sragovich at the Miriam and Sheldon G. Adelson Graduate School of Medicine, Sackler Faculty of Medicine, Tel Aviv University. We thank Orly Yaron, Genome Center Laboratory, Limor Frish, NMR Laboratory, and Yael Piontkewitz, Alfredo Federico Strauss Center for Computational Neuroimaging at Tel Aviv University and the Technion's Genomic Center for their input and excellent work. We thank Oxana Kapitansky for her help.

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  1. N Amram and G Hacohen-Kleiman: These authors contributed equally to this work.

Authors and Affiliations

  1. Lily and Avraham Gildor Chair for the Investigation of Growth Factors; Elton Laboratory for Neuroendocrinology; Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Sagol School of Neuroscience and Adams Super Center for Brain Studies, Tel Aviv University,

    N Amram, G Hacohen-Kleiman, S Sragovich, A Malishkevich, J Katz, E Giladi, Y Jouroukhin & I Gozes

  2. Elton Laboratory for Neuroendocrinology, Tel Aviv, Israel

    N Amram, G Hacohen-Kleiman, S Sragovich, A Malishkevich, J Katz, E Giladi, Y Jouroukhin & I Gozes

  3. Department of Neurology, Laboratory of Experimental Neurology, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece

    O Touloumi, R Lagoudaki & N C Grigoriadis

  4. Bioinformatics Unit, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel

    A Yeheskel & M Pasmanik-Chor

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SKIP is under patent protection and under term sheet agreement to Coronis Partners (IG conflict of interest).

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Amram, N., Hacohen-Kleiman, G., Sragovich, S. et al. Sexual divergence in microtubule function: the novel intranasal microtubule targeting SKIP normalizes axonal transport and enhances memory. Mol Psychiatry 21, 1467–1476 (2016). https://doi.org/10.1038/mp.2015.208

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