title: Sexual divergence in microtubule function: the novel intranasal microtubule targeting SKIP normalizes axonal transport and enhances memory.
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.
authors.affiliation: 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, Tel Aviv, Israel.
authors.forename: N
authors.initials: N
authors.lastname: Amram
authors.affiliation: 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, Tel Aviv, Israel.
authors.forename: G
authors.initials: G
authors.lastname: Hacohen-Kleiman
authors.affiliation: 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, Tel Aviv, Israel.
authors.forename: S
authors.initials: S
authors.lastname: Sragovich
authors.affiliation: 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, Tel Aviv, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Malishkevich
authors.affiliation: 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, Tel Aviv, Israel.
authors.forename: J
authors.initials: J
authors.lastname: Katz
authors.affiliation: Department of Neurology, Laboratory of Experimental Neurology, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: O
authors.initials: O
authors.lastname: Touloumi
authors.affiliation: Department of Neurology, Laboratory of Experimental Neurology, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: R
authors.initials: R
authors.lastname: Lagoudaki
authors.affiliation: Department of Neurology, Laboratory of Experimental Neurology, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: N C
authors.initials: NC
authors.lastname: Grigoriadis
authors.affiliation: 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, Tel Aviv, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Giladi
authors.affiliation: Bioinformatics Unit, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Yeheskel
authors.affiliation: Bioinformatics Unit, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Pasmanik-Chor
authors.affiliation: 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, Tel Aviv, Israel.
authors.forename: Y
authors.initials: Y
authors.lastname: Jouroukhin
authors.affiliation: 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, Tel Aviv, Israel.
authors.forename: I
authors.initials: I
authors.lastname: Gozes
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D000067877:Autism Spectrum Disorder / Q000209:etiology / Q000235:genetics; D001370:Axonal Transport / Q000235:genetics / Q000502:physiology; D001921:Brain / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D020908:Calcium Channels, R-Type / Q000235:genetics / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D049229:Dendritic Spines / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008568:Memory; D051379:Mice; D008870:Microtubules / Q000378:metabolism / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012737:Sex Factors; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000378:metabolism
chemical_list: C117632:Adnp protein, mouse; C498916:Cacna1e protein, mouse; D015220:Calcium Channels; D020908:Calcium Channels, R-Type; D027682:Cation Transport Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D014404:Tubulin; D050257:Tubulin Modulators