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Published on: December 10, 2013
Dramatic sex differences leading to different brain disease presentation: The requirement for sex-specific
Alexandra Lobyntseva1, Liri Sophia Guz2, Artur Galushkin1
1The Elton Laboratory for Molecular Neuroendocrinology, Department of Human Genetics and Computational Medicine, Gray Faculty of Medical and Health Sciences, Sagol School of Neuroscience and Adams Super Center for Brain Studies, Tel Aviv University, Tel Aviv 6997801, Israel; Department of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela, Santiago de Compostela, Spain.
Abstract:
Focusing on the brain-essential gene revealed in our laboratory, activity-dependent neuroprotective protein (ADNP) and its neuroprotective site, the investigational drug davunetide (NAP), we discuss ADNP regulating steroid hormone biosynthesis and sex chromosome genes coupled with sex-dependent shuttling between the nuclei and cytoplasm. Further coupled with sex-dependent transcriptional control, ADNP/davunetide cytoplasmic microtubule/Tau targeting is translated into differential sex regulation of key cellular processes including neurogenesis, synaptic function, and axonal transport, then decoded into sexual dichotomy in multicellular processes directing sex-dependent behavioral outcomes. ADNP regulation of these sex-specific processes serves as a target for davunetide intervention, toward sex-directed precision medicine, revealing sexually dichotomized neuroprotection against tauopathy risk and progression spanning from coronary artery bypass grafting (CABG) to prodromal Alzheimer's disease, progressive supranuclear palsy (PSP), and schizophrenia, as well as the pediatric ADNP syndrome. Sex-specific intranasal bioavailability of davunetide, regulated by the estrous cycle, provides a mechanistic foundation for these differential outcomes.
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