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

Adva Hadar, Oxana Kapitansky, Maram Ganaiem, Shlomo Sragovich, Alexandra Lobyntseva, Eliezer Giladi, Adva Yeheskel, Aliza Avitan, Gad D Vatine, David Gurwitz, Yanina Ivashko-Pachima, Illana Gozes

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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.

Original languageEnglish
Pages (from-to)6550-6561
Number of pages12
JournalMolecular Psychiatry
Volume26
DOIs
StatePublished - 10 May 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health

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