Shapira Guy, Karmon Gidon, Hacohen-Kleiman Gal, Ganaiem Maram, Shazman Shula, Theotokis Paschalis, Grigoriadis Nikolaos, Shomron Noam, Gozes Illana
Department of Cell and Developmental Biology, Faculty of Medical and Health Sciences, Sagol School of Neuroscience, Edmond J Safra Center for Bioinformatics, Tel Aviv University, Tel Aviv, 6997801, Israel.
Elton Laboratory for Molecular Neuroendocrinology, Department of Human Molecular Genetics and Biochemistry, Faculty of Medical and Health Sciences, Adams Super Center for Brain Studies and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 6997801, Israel.
Mol Psychiatry. 2025 Jun;30(6):2696-2706. doi: 10.1038/s41380-024-02879-w. Epub 2024 Dec 23.
Essential for brain formation and protective against tauopathy, activity-dependent neuroprotective protein (ADNP) is critical for neurogenesis and cognitive functions, while regulating steroid hormone biogenesis. As such, de novo mutations in ADNP lead to syndromic autism and somatic ADNP mutations parallel Alzheimer's disease progression. Furthermore, clinical trials with the ADNP fragment NAP (the investigational drug davunetide) showed efficacy in women suffering from the tauopathy progressive supranuclear palsy and differentially boosted memory in men (spatial) and women (verbal), exhibiting prodromal Alzheimer's disease. While autism is more prevalent in boys and Alzheimer's disease in women, both involve impaired neurogenesis. Here, we asked whether ADNP sex-dependently regulates neurogenesis. Using bromodeoxyuridine (BrdU) as a marker of neurogenesis, we identified two-fold higher labeling in the hippocampal sub-ventricular zone of ADNP-intact male versus female mice. Adnp haplo-insufficient (Adnp) mice or mice CRSIPR/Cas9-edited to present the most prevalent neurodevelopmental ADNP syndrome mutation, p.Tyr718* (Tyr) showed dramatic reductions in male BrdU incorporation, resulting in mutated females presenting higher labeling than males. Treatment with NAP compensated for the male reduction of BrdU labeling. Mechanistically, hippocampal RNAseq revealed male-specific Tyr down-regulation of endoplasmic reticulum unfolded protein response genes critical for sex-dependent organogenesis. Newly discovered mitochondrial accessibility of ADNP was inhibited by the Tyr718* mutation further revealing female-specific Tyr downregulation of mitochondrial ATP6. NAP moderated much of the differential expression caused by p.Tyr718*, accompanied by the down-regulation of neurotoxic, pro-inflammatory and pro-apoptotic genes. Thus, ADNP is a key regulator of sex-dependent neurogenesis that acts by controlling canonical pathways, with NAP compensating for fundamental ADNP deficiencies, striding toward clinical development targeting the ADNP syndrome and related neurodevelopmental/neurodegenerative diseases.
活性依赖的神经保护蛋白（ADNP）对大脑形成至关重要，可预防tau蛋白病，对神经发生和认知功能至关重要，同时调节类固醇激素生物合成。因此，ADNP的新生突变会导致综合征性自闭症，而体细胞ADNP突变与阿尔茨海默病进展平行。此外，ADNP片段NAP（研究性药物达武奈肽）的临床试验表明，它对患有tau蛋白病进行性核上性麻痹的女性有效，并且在男性（空间记忆）和女性（语言记忆）中差异增强记忆，表现出前驱性阿尔茨海默病。虽然自闭症在男孩中更普遍，阿尔茨海默病在女性中更常见，但两者都涉及神经发生受损。在这里，我们询问ADNP是否以性别依赖的方式调节神经发生。使用溴脱氧尿苷（BrdU）作为神经发生的标志物，我们发现完整ADNP的雄性小鼠海马脑室下区的标记比雌性小鼠高两倍。Adnp单倍体不足（Adnp）小鼠或经CRSIPR/Cas9编辑以呈现最常见的神经发育性ADNP综合征突变p.Tyr718*（Tyr）的小鼠，雄性BrdU掺入量显著降低，导致突变的雌性小鼠比雄性小鼠呈现更高的标记。用NAP治疗可补偿雄性BrdU标记的减少。从机制上讲，海马RNA测序揭示了内质网未折叠蛋白反应基因的雄性特异性Tyr下调，这些基因对性别依赖的器官发生至关重要。新发现的ADNP的线粒体可及性被Tyr718突变抑制，进一步揭示了线粒体ATP6的雌性特异性Tyr下调。NAP减轻了由p.Tyr718引起的许多差异表达，同时下调了神经毒性、促炎和促凋亡基因。因此，ADNP是性别依赖神经发生的关键调节因子，通过控制经典途径发挥作用，NAP可补偿ADNP的基本缺陷，朝着针对ADNP综合征及相关神经发育/神经退行性疾病的临床开发迈进。
