title: ADNP/NAP dramatically increase microtubule end-binding protein-Tau interaction: a novel avenue for protection against tauopathy.
abstract: Activity-dependent neuroprotective protein (ADNP), vital for brain formation and cognitive function, is mutated in autism and linked to neurodegenerative/psychiatric diseases. An eight-amino-acid peptide snippet of ADNP, NAP (NAPVSIPQ), identified as a smallest active fragment, includes the SxIP microtubule (MT) end-binding protein (EB) association motif, and enhances ADNP-EB3 interaction. Depletion of EB1 or EB3 abolishes NAP protection against zinc intoxication. Furthermore, NAP enhances Tau-MT interaction, and Tau regulates the localization and function of EB1 and EB3 in developing neuronal cells. Here, we asked how NAP (ADNP) enhances Tau-MT interactions and whether this is mediated by EBs. We showed, for we believe the first time, that NAP augmented endogenous EB1 comet density in the N1E-115 neuroblastoma neuronal model. This finding was substantiated by cell transfection with fluorescent EB1 and live cell imaging. NAP increased comet amounts, length and speed. At the molecular level, NAP enhanced EB3 homodimer formation, while decreasing EB1-EB3 heterodimer content and driving EB1- and EB3-Tau interactions (dramatic 20-fold increases), leading to recruitment of EB1/EB3 and Tau to MTs under zinc intoxication. Our previous results showed that while NAP protected neuronal-like cells against oxidative stress, it did not protect NIH3T3 fibroblasts. Here, NAP did not protect NIH3T3 cells against zinc intoxication, unless these cells were transfected with Tau. Interestingly, other MT associated proteins (MAPs) may replace Tau, thus, EB-Tau (MAPs) interaction is identified as a novel target for endogenous ADNP neuroprotection, and a future target for drug development, with NAP as a prototype.
authors.affiliation: The Lily and Avraham Gildor Chair for the Investigation of Growth Factors, Dr. Diana and Zelman Elton (Elbaum) Laboratory for Molecular 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: Ivashko-Pachima
authors.affiliation: Centre for Biomedical Research of the Canary Islands (CIBICAN), Institute for Biomedical Technologies (ITB), University of La Laguna (ULL), Tenerife, Spain.
authors.forename: C Laura
authors.initials: CL
authors.lastname: Sayas
authors.affiliation: The Lily and Avraham Gildor Chair for the Investigation of Growth Factors, Dr. Diana and Zelman Elton (Elbaum) Laboratory for Molecular 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: The Lily and Avraham Gildor Chair for the Investigation of Growth Factors, Dr. Diana and Zelman Elton (Elbaum) Laboratory for Molecular 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: D000818:Animals; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009842:Oligopeptides; D010455:Peptides; D011485:Protein Binding / Q000502:physiology; D024801:Tauopathies / Q000628:therapy; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C117632:Adnp protein, mouse; C584107:EB1 protein, mouse; C522423:EB3 protein, mouse; D018398:Homeodomain Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009842:Oligopeptides; D010455:Peptides; D016875:tau Proteins