TY - JOUR
T1 - Sexual divergence in microtubule function
T2 - The novel intranasal microtubule targeting SKIP normalizes axonal transport and enhances memory
AU - Amram, N.
AU - Hacohen-Kleiman, G.
AU - Sragovich, S.
AU - Malishkevich, A.
AU - Katz, J.
AU - Touloumi, O.
AU - Lagoudaki, R.
AU - Grigoriadis, N. C.
AU - Giladi, E.
AU - Yeheskel, A.
AU - Pasmanik-Chor, M.
AU - Jouroukhin, Y.
AU - Gozes, I.
N1 - Publisher Copyright:
© 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
PY - 2016/10/1
Y1 - 2016/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84954561845&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84954561845&partnerID=8YFLogxK
U2 - 10.1038/mp.2015.208
DO - 10.1038/mp.2015.208
M3 - Article
C2 - 26782054
AN - SCOPUS:84954561845
SN - 1359-4184
VL - 21
SP - 1467
EP - 1476
JO - Molecular psychiatry
JF - Molecular psychiatry
IS - 10
ER -