The NAP motif of activity-dependent neuroprotective protein (ADNP) regulates dendritic spines through microtubule end binding proteins

S. Oz, O. Kapitansky, Y. Ivashco-Pachima, A. Malishkevich, E. Giladi, N. Skalka, R. Rosin-Arbesfeld, L. Mittelman, O. Segev, J. A. Hirsch, I. Gozes*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The NAP motif of activity-dependent neuroprotective protein (ADNP) enhanced memory scores in patients suffering from mild cognitive impairment and protected activities of daily living in schizophrenia patients, while fortifying microtubule (MT)-dependent axonal transport, in mice and flies. The question is how does NAP fortify MTs? Our sequence analysis identified the MT end-binding protein (EB1)-interacting motif SxIP (SIP, Ser-Ile-Pro) in ADNP/NAP and showed specific SxIP binding sites in all members of the EB protein family (EB1-3). Others found that EB1 enhancement of neurite outgrowth is attenuated by EB2, while EB3 interacts with postsynaptic density protein 95 (PSD-95) to modulate dendritic plasticity. Here, NAP increased PSD-95 expression in dendritic spines, which was inhibited by EB3 silencing. EB1 or EB3, but not EB2 silencing inhibited NAP-mediated cell protection, which reflected NAP binding specificity. NAPVSKIPQ (SxIP = SKIP), but not NAPVAAAAQ mimicked NAP activity. ADNP, essential for neuronal differentiation and brain formation in mouse, a member of the SWI/SNF chromatin remodeling complex and a major protein mutated in autism and deregulated in schizophrenia in men, showed similar EB interactions, which were enhanced by NAP treatment. The newly identified shared MT target of NAP/ADNP is directly implicated in synaptic plasticity, explaining the breadth and efficiency of neuroprotective/neurotrophic capacities.

Original languageEnglish
Pages (from-to)1115-1124
Number of pages10
JournalMolecular Psychiatry
Volume19
Issue number10
DOIs
StatePublished - 1 Oct 2014

Funding

FundersFunder number
Adams family
Allon Therapeutics Inc.
Oberfeld family
AAMN Foundation
Tel Aviv University

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