title: The NAP motif of activity-dependent neuroprotective protein (ADNP) regulates dendritic spines through microtubule end binding proteins.
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.
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: S
authors.initials: S
authors.lastname: Oz
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: O
authors.initials: O
authors.lastname: Kapitansky
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Y
authors.initials: Y
authors.lastname: Ivashco-Pachima
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Malishkevich
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Giladi
authors.affiliation: Department of Anatomy, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: N
authors.initials: N
authors.lastname: Skalka
authors.affiliation: Department of Anatomy, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: R
authors.initials: R
authors.lastname: Rosin-Arbesfeld
authors.affiliation: Department of Interdepartmental Services, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: L
authors.initials: L
authors.lastname: Mittelman
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel [2] Sagol School of Neuroscience and Adams Super Center for Brain Studies, Tel Aviv University, Tel Aviv, Israel.
authors.forename: O
authors.initials: O
authors.lastname: Segev
authors.affiliation: Department of Biochemistry and Molecular Biology, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: J A
authors.initials: JA
authors.lastname: Hirsch
authors.affiliation: 1] Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel [2] 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: D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D049229:Dendritic Spines / Q000502:physiology*; D000076122:Disks Large Homolog 4 Protein; D004926:Escherichia coli; D051528:Guanylate Kinases / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000502:physiology; D016716:PC12 Cells; D054730:Protein Interaction Domains and Motifs; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism
chemical_list: C579795:ADNP protein, rat; C117632:Adnp protein, mouse; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; C501449:Dlg4 protein, rat; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; C500985:MAPRE1 protein, human; C403664:MAPRE3 protein, human; C561584:Mapre1 protein, rat; C534832:Mapre3 protein, rat; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; D014404:Tubulin; D051528:Guanylate Kinases