AD7C-NTP信号蛋白抑制MeCP2 S421特异位点磷酸化 调控阿尔茨海默病神经再生的表观遗传学机制

Alzheimer’s disease (AD) has become a serious disease hazarding the people’s health, whose pathogenesis is not clear and would induce serious injuries to the neural cells. The preliminary results of the applicant have confirmed that lineage specific gene expression, which is responsible for the proliferation and differentiation of neural stem/progenitor cells(NSCs/NPCs), plays an important role in the neural regeneration of AD. In AD mice brain, the expression levels of lineage specific genes (such as Gfap、Nestin and Dcx ) are very low, and are negatively correlated with an important signal protein AD7C-NTP in the course of the disease. Inhibition of AD7C-NTP can promote these neural lineage specific gene transcription and neurogenesis. Site-specific phosphorylation of the epigenetic regulatory protein MeCP2 at Serine 421(S421) can initiate its translocation from nucleus to cytoplasm, release chromatin configuration and promote gene transcription, which is a key event in mediating the intervention effect of AD7C-NTP on neural regeneration. The deprival of S421 site-specific phosphorylation will attenuate the pathogenicity of AD7C-NTP. In conclusion, we propose that AD7C-NTP signal protein will accelerate the progress of AD by promoting apoptosis and inhibiting neural regeneration. Its pathogenic role is presumed to be mediated, in part, through suppressing the phosphorylation of MeCP2 at S421 and subsequently a list of lineage specific gene expression and synaptic plasticity. This study is expected to provide scientific basis and theoretical basis for the development of biological markers and drug targets for early diagnosis and treatment of AD.

阿尔茨海默病（AD）已成为危害健康的重大疾病，发病机制未明，可致神经细胞严重受损。申请人前期结果表明，调控指导神经干/祖细胞增殖和分化的特异性基因表达对AD神经再生有重要作用。神经细胞特异性标记基因Gfap、Nestin和Dcx在AD脑内低表达，且与疾病进程中的重要信号蛋白AD7C-NTP表达呈负相关，抑制该蛋白可促进上述基因转录及神经再生。表观遗传调节蛋白MeCP2 S421特异位点磷酸化可启动MeCP2核浆转位，松解染色质构型，促进基因转录，是介导AD7C-NTP干预神经再生的关键事件。剥夺该位点磷酸化修饰则削弱AD7C-NTP的致病作用。故我们提出AD7C-NTP通过抑制MeCP2 S421特异位点磷酸化，从表观遗传学水平调控神经细胞特异性基因表达及突触可塑性，实现对神经细胞促凋亡、抑再生作用，加速AD进展。本研究有望为开发AD早期诊疗的生物学标记物及药物靶点提供科学依据与理论基础。

阿尔茨海默病（AD）已成为危害健康的重大疾病，发病机制未明，可导致神经细胞严重受损。管AD损伤后神经再生的重要作用已日渐显现，但新生的神经元能否在形态上和电生理功能上发育成熟并长期存活，迁移并整合到受损部位，发挥损伤修复作用？尚有待进一步研究证实。因此，调控SVZ区NSCs/NPCs再生和分化方向的具体分子机制是AD研究中正在探索、亟待解决的重点领域。我们前期结果表明，调控指导神经干/祖细胞增殖和分化的特异性基因表达对AD神经再生有重要作用。该研究证实神经细胞特异性标记基因Gfap、Nestin和Dcx在AD脑内低表达，且与疾病进程中的重要信号蛋白AD7C-NTP表达呈负相关，抑制该蛋白可促进上述基因转录及神经再生。表观遗传调节蛋白MeCP2 S421特异位点磷酸化可启动MeCP2核浆转位，松解染色质构型，促进基因转录，是介导AD7C-NTP干预神经再生的关键事件。反之推测，剥夺该位点磷酸化修饰则削弱AD7C-NTP的致病作用。故提出AD7C-NTP通过抑制MeCP2 S421特异位点磷酸化，从表观遗传学水平调控神经细胞特异性基因表达及突触可塑性，实现对神经细胞促凋亡、抑再生作用，加速AD进展。同时总结不同临床阶段AD患者各体液标本中AD7C-NTP的表达特点，阐明AD7C-NTP与AD患者脑组织病变、认知功能障碍的关联。本研究为将AD7C-NTP开发为AD的早期诊断标记物、病情评价指标以及潜在干预靶点提供科学依据与理论基础。