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Introducing ADNP and SIRT1 as new partners regulating microtubules and histone methylation

Molecular Psychiatry volume 26, pages 6550–6561 (2021)Cite this article

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Abstract

Activity-dependent neuroprotective protein (ADNP) is essential for brain formation and function. As such, de novo mutations in ADNP lead to the autistic ADNP syndrome and somatic ADNP mutations may drive Alzheimer’s disease (AD) tauopathy. Sirtuin 1 (SIRT1) is positively associated with aging, the major risk for AD. Here, we revealed two key interaction sites for ADNP and SIRT1. One, at the microtubule end-binding protein (EB1 and EB3) Tau level, with EB1/EB3 serving as amplifiers for microtubule dynamics, synapse formation, axonal transport, and protection against tauopathy. Two, on the DNA/chromatin site, with yin yang 1, histone deacetylase 2, and ADNP, sharing a DNA binding motif and regulating SIRT1, ADNP, and EB1 (MAPRE1). This interaction was linked to sex- and age-dependent altered histone modification, associated with ADNP/SIRT1/WD repeat-containing protein 5, which mediates the assembly of histone modification complexes. Single-cell RNA and protein expression analyses as well as gene expression correlations placed SIRT1–ADNP and either MAPRE1 (EB1), MAPRE3 (EB3), or both in the same mouse and human cell; however, while MAPRE1 seemed to be similarly regulated to ADNP and SIRT1, MAPRE3 seemed to deviate. Finally, we demonstrated an extremely tight correlation for the gene transcripts described above, including related gene products. This correlation was specifically abolished in affected postmortem AD and Parkinson’s disease brain select areas compared to matched controls, while being maintained in blood samples. Thus, we identified an ADNP–SIRT1 complex that may serve as a new target for the understanding of brain degeneration.

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Fig. 1: ADNP interacts with SIRT1.
Fig. 2: RNA-seq identification of ADNP–SIRT1 co-localization at the human single-cell level.
Fig. 3: ADNP and SIRT1 are co-regulated at the transcriptional level and both control specific histone H3 modifications.
Fig. 4: ADNP and SIRT1 correlate and interact with histone remodeling complex proteins.
Fig. 5: Marked dysregulation in AD postmortem brains, the ADNP/SIRT1 network.

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Acknowledgements

This work was partially supported by the following grants (IG): European Research Area Network (ERA-NET) Neuron ADNPinMED, the US–Israel Binational Science Foundation—US National Science Foundation (BSF-NSF 2016746), the Alberto Moscona Nisim (AMN) Foundation for the Advancement of Science, Art and Culture in Israel, as well as by Drs. Ronith and Armand Stemmer and Arthur Gerbi (French Friends of Tel Aviv University) and Anne and Alex Cohen (Canadian Friends of Tel Aviv University). OK and SS were supported by the Israeli BioInnovators Fellowship and Mentorship by Teva. SS is a former Levi Eshkol fellow supported by the Israel Ministry of Science and Technology, and a former awardee of the Tel Aviv University GRTF and The Naomi Foundation, as well as The Eldee Foundation/Bloomfield Family of Montreal awards for student exchange (Tel Aviv University/McGill University). YI-P was supported in part by the Aufzien Family Center for the Prevention and Treatment of Parkinson’s Disease (APPD) postdoctoral fellowship. This work is in partial fulfillment of OK and MG (PhD) and AL (MSc), respective thesis requirements at the Dr. Miriam and Sheldon G. Adelson Graduate School of Medicine, Sackler Faculty of Medicine, Tel Aviv University. We thank Gal Hacohen-Kleiman and Gidon Karmon for their help with Adnp+/– mouse colony as well as Prof. Rina Meidan and Jackson Sapuleni for the AB_2285964 SIRT1 validation antibodies.

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  1. These authors contributed equally: Adva Hadar, Oxana Kapitansky

Authors and Affiliations

  1. The Elton Laboratory for Neuroendocrinology, Sackler Faculty of Medicine, Sagol School of Neuroscience and Adams Super Center for Brain Studies, Tel Aviv University, Tel Aviv, Israel

    Adva Hadar, Oxana Kapitansky, Maram Ganaiem, Shlomo Sragovich, Alexandra Lobyntseva, Eliezer Giladi, Yanina Ivashko-Pachima & Illana Gozes

  2. 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

    Adva Hadar, Oxana Kapitansky, Maram Ganaiem, Shlomo Sragovich, Alexandra Lobyntseva, Eliezer Giladi, David Gurwitz, Yanina Ivashko-Pachima & Illana Gozes

  3. Weizmann Institute of Science, Rehovot, Israel

    Adva Hadar

  4. Bioinformatics Unit, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel

    Adva Yeheskel

  5. The Department of Physiology and Cell Biology, Faculty of Health Sciences, The Regenerative Medicine and Stem Cell (RMSC) Research Center and the Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, Israel

    Aliza Avitan & Gad D. Vatine

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NAP (CP201) use is under patent protection (US patent nos. US7960334, US8618043, US10912819) and provisional patent applications, Ramot at Tel Aviv University.

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Hadar, A., Kapitansky, O., Ganaiem, M. et al. Introducing ADNP and SIRT1 as new partners regulating microtubules and histone methylation. Mol Psychiatry 26, 6550–6561 (2021). https://doi.org/10.1038/s41380-021-01143-9

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