Behind the paper: ADNP is essential for sex-dependent hippocampal neurogenesis, through male unfolded protein response and female mitochondrial gene regulation
Discovered in our laboratory, activity-dependent neuroprotective protein (ADNP) is essential for neurodevelopment and de novo mutations in ADNP cause the autistic ADNP syndrome. Furthermore, somatic mutations in ADNP parallel Alzheimer’s disease progression and cognitive decline. Given the strong impact of ADNP on cognitive functions, intimately involved with neurogenesis, we investigated mouse models of the ADNP syndrome. Using a marker of neurogenesis, we identified two-fold higher labeling in the main brain area of adult neurogenesis responsible for learning and memory (namely, the hippocampal sub-ventricular zone) of ADNP-intact male compared to female mice. Transgenic mice having only one copy (instead of two copies) of the ADNP gene or genome-edited mice, presenting the most prevalent neurodevelopmental ADNP syndrome mutation, showed dramatic reductions in male neurogenesis, resulting in mutated females presenting higher neurogenesis than males. Treatment with the ADNP neuroprotective fragment called NAP (now, the investigational drug davunetide) compensated for the male reduction of neurogenesis. In depth analysis of all genes expressed in this important brain area in the ADNP syndrome genome-edited mice revealed male-specific downregulation of genes involved in maintaining healthy protein structure (namely unfolded protein response genes) critical for sex-dependent organogenesis. Contrastingly, in females, a major protein responsible for providing energy in the energy centers of the cells (called mitochondria, inherited from mothers, and further linked with autism and Alzheimer’s disease) was discovered as regulated by ADNP/davunetide. Davunetide moderated much of the differential expression caused by the genome-edited ADNP mutation. In this respect, we have recently discovered that davunetide sex-dependently boosts memory in individuals at risk for Alzheimer's disease as well as in women suffering from progressive supranuclear palsy (PSP) sharing similar pathology with Alzheimer’s disease and with the ADNP syndrome. Importantly, the unfolded protein response is dysregulated in Alzheimer's disease as well as in PSP, thus, affecting disease severity. Our current discoveries of ADNP/davunetide sex-dependent regulation of the unfolded protein response pathway in association with regulation of X-chromosome linked genes and sex steroid hormone biosynthesis explain the significant sex-dependent davunetide efficacy. As such, davunetide is now planned for immediate clinical development in women suffering from PSP and in children suffering from the ADNP syndrome, led by Exonavis Therapeutics Ltd (Professor Illana Gozes, Vice President, Drug Development).
The study was led by Professor Illana Gozes, Faculty of Medical and Health Sciences, Adams Super Center for Brain Studies and Sagol School of Neuroscience, Tel Aviv University, together with PhD student, Guy Shapira (co-first author), mentored by Professor Noam Shomron, Dr. Gidon Karmon (co-first author) and Dr. Gal Hacohen-Kleiman (former PhD students with Professor Gozes), Maram Ganaiem (PhD student with Professor Gozes), Dr. Shula Shazman (Open University, Israel) and Dr. Paschalis Theotokis and Professor Nikolaos Grigoriadis, Aristotle University of Thessaloniki, Thessaloniki, Greece
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Molecular Psychiatry
This journal publishes work aimed at elucidating biological mechanisms underlying psychiatric disorders and their treatment, with emphasis on studies at the interface of pre-clinical and clinical research.
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