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ADNP/NAP dramatically increase microtubule end-binding protein–Tau interaction: a novel avenue for protection against tauopathy

Molecular Psychiatry volume 22, pages 1335–1344 (2017)Cite this article

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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.

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Acknowledgements

We are grateful to Drs Stella Aronov, Department of Molecular Biology, Ariel University, Ariel, Israel; Doron Chabat, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv, Israel and Eran Perlson, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel, for providing valuable reagents, including the Tau plasmid, the labeled NAP and the EMTB plasmid, respectively. Professor Gozes Laboratory is supported in part by the AMN Foundation, Israel Science Foundation, ERA-NET-NEURON, the Dr. Diana and Zelman Elton (Elbaum) Laboratory for Molecular Neuroendocrinology and the Lily and Avraham Gildor Chair for the Investigation of Growth Factors at Tel Aviv University. YI-P is supported by a Joseph Sagol PhD fellowship in brain studies, in the Dr. Miriam and Sheldon Adelson Graduate School at the Sackler Faculty of Medicine, Tel Aviv University. CLS was supported by the IMBRAIN project (FP7-REGPOT-2012-CT2012–31637-IMBRAIN), funded under the 7th Framework Programme (Capacities).

Author contributions

YI-P designed and performed the work; CLS provided the neuroblastoma cell line and in-depth knowhow for EB imaging; AM provided knowhow for immunoprecipitations and IG supervised the work and guided research plans and manuscript preparation.

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  1. Department of Human Molecular Genetics and Biochemistry, The Lily and Avraham Gildor Chair for the Investigation of Growth Factors, Dr. Diana and Zelman Elton (Elbaum) Laboratory for Molecular Neuroendocrinology, Sackler Faculty of Medicine, Sagol School of Neuroscience and Adams Super Center for Brain Studies, Tel Aviv University, Tel Aviv, Israel

    Y Ivashko-Pachima, A Malishkevich & I Gozes

  2. Centre for Biomedical Research of the Canary Islands (CIBICAN), Institute for Biomedical Technologies (ITB), University of La Laguna (ULL), Tenerife, Spain

    C Laura Sayas

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Correspondence to I Gozes.

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NAP is under patent protection and term sheet agreement (Ramot at the Tel Aviv University and Coronis Neurosciences, Israel; IG, the inventor and Chief Scientific Officer). The remaining authors declare no conflict of interest.

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Ivashko-Pachima, Y., Sayas, C., Malishkevich, A. et al. ADNP/NAP dramatically increase microtubule end-binding protein–Tau interaction: a novel avenue for protection against tauopathy. Mol Psychiatry 22, 1335–1344 (2017). https://doi.org/10.1038/mp.2016.255

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