ADNP通过雄性未折叠蛋白反应和雌性线粒体基因调控对性别依赖性海马神经发生至关重要

IF 9.6 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Psychiatry Pub Date : 2024-12-23 DOI:10.1038/s41380-024-02879-w
Guy Shapira, Gidon Karmon, Gal Hacohen-Kleiman, Maram Ganaiem, Shula Shazman, Paschalis Theotokis, Nikolaos Grigoriadis, Noam Shomron, Illana Gozes
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引用次数: 0

摘要

活动依赖性神经保护蛋白(activity-dependent neuroprotective protein, ADNP)对脑的形成和防止牛头病至关重要,在调节类固醇激素生物发生的同时,对神经发生和认知功能至关重要。因此,ADNP的新生突变导致综合征性自闭症,而体细胞ADNP突变与阿尔茨海默病的进展相似。此外,ADNP片段NAP(研究药物达文尼肽)的临床试验显示,对患有tau病进行性核上性麻痹的女性有效,并在男性(空间)和女性(言语)中不同程度地增强了记忆,表现出前驱阿尔茨海默病。虽然自闭症在男孩中更为普遍,阿尔茨海默病在女性中更为普遍,但两者都涉及神经发生受损。在这里,我们询问ADNP是否依赖性别调节神经发生。使用溴脱氧尿苷(BrdU)作为神经发生的标记物,我们发现在adnp完整的雄性小鼠海马脑室下区标记比雌性小鼠高两倍。Adnp单倍体不足(Adnp+/−)小鼠或CRSIPR/ cas9编辑小鼠呈现最普遍的神经发育Adnp综合征突变p.Tyr718* (Tyr)显示雄性BrdU掺入显著减少,导致突变的雌性比雄性表现出更高的标记。NAP治疗补偿了男性BrdU标记的减少。机制上,海马RNAseq揭示了男性特异性Tyr下调内质网未折叠蛋白反应基因,这对性别依赖性器官发生至关重要。新发现的线粒体ADNP可及性被Tyr718*突变抑制,进一步揭示了女性特异性的Tyr下调线粒体ATP6。NAP可抑制p.Tyr718*引起的差异表达,并伴有神经毒性、促炎和促凋亡基因的下调。因此,ADNP是性别依赖性神经发生的关键调节因子,通过控制规范通路起作用,NAP补偿基本的ADNP缺陷,朝着针对ADNP综合征和相关神经发育/神经退行性疾病的临床发展迈进。
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ADNP is essential for sex-dependent hippocampal neurogenesis, through male unfolded protein response and female mitochondrial gene regulation

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.

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来源期刊
Molecular Psychiatry
Molecular Psychiatry 医学-精神病学
CiteScore
20.50
自引率
4.50%
发文量
459
审稿时长
4-8 weeks
期刊介绍: Molecular Psychiatry focuses on publishing research that aims to uncover the biological mechanisms behind psychiatric disorders and their treatment. The journal emphasizes studies that bridge pre-clinical and clinical research, covering cellular, molecular, integrative, clinical, imaging, and psychopharmacology levels.
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