Sexual divergence in microtubule function: the novel intranasal microtubule targeting SKIP normalizes axonal transport and enhances memory.
Τίτλος | Sexual divergence in microtubule function: the novel intranasal microtubule targeting SKIP normalizes axonal transport and enhances memory. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | 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. |
Journal | Mol Psychiatry |
Volume | 21 |
Issue | 10 |
Pagination | 1467-76 |
Date Published | 2016 10 |
ISSN | 1476-5578 |
Λέξεις κλειδιά | Amino Acid Motifs, Animals, Autism Spectrum Disorder, Axonal Transport, Brain, Calcium Channels, Calcium Channels, R-Type, Cation Transport Proteins, Dendritic Spines, Female, Hippocampus, Homeodomain Proteins, Male, Memory, Mice, Microtubules, Nerve Tissue Proteins, RNA, Messenger, Sex Factors, Tubulin, Tubulin Modulators |
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. |
DOI | 10.1038/mp.2015.208 |
Alternate Journal | Mol. Psychiatry |
PubMed ID | 26782054 |