SR蛋白在大脑脂代谢以及阿尔茨海默病病理过程中的作用机制研究

Serine/arginine (SR) proteins are a highly conserved class of RNA binding proteins, they are extensively characterized for their activities in post-transcriptional regulations, including mRNA splicing, metabolism, nuclear export and translation. SR proteins serve as a pivotal regulator of mRNA metabolism in both physiological and pathological process. Lipid metabolism is highly involved in learning memory and AD pathology, however, the relationship between SR proteins and lipid metabolism remains largely unknown, especially how certain SR proteins participate in AD pathology by regulating lipid metabolism. Based on preliminary data we hypothesize that SR protein participates in AD pathology by modulating lipid metabolism in brain. Our primary research goals are: 1) A comprehensive evaluation of SR proteins level in AD or control brains, and significantly differentially expressed ones will be selected, among those whose level change is correlated to lipid metabolism. 2) To uncover the cellular and molecular mechanism by which selected SR proteins regulates lipid metabolism, including lipid synthesis and secretion by astrocytes, and uptake and utilization by neurons. 3) To define how target SR proteins affect neuron/synapse functions，Aβmetabolism and AD pathological processes by regulating lipid metabolism. Given the unique features of lipid metabolism in brains, it is essential to illustrate the SR protein functions in lipid metabolism process of astrocytes and neurons respectively. This will guide us to deeply understand the regulation network of SR proteins, and how they coordinately work in neurons and astrocytes, ultimately affect AD pathobiology. Our research will provide possibility of novel therapeutic targets for AD.

SR蛋白是一类RNA结合蛋白，主要参与mRNA的剪切、代谢、转运以及翻译等基因转录后调控，在许多生理及病理中起关键调控作用。脂代谢在学习记忆以及AD病理中起重要作用，但SR蛋白和脂代谢的内在关联，尤其是在AD病理过程中的作用并不清楚。基于前期结果我们假设：SR蛋白通过调控大脑脂代谢参与AD病理进程。本研究目标: 1）全面评价SR蛋白在AD病理过程中的差异表达，筛选和脂代谢调控相关的SR蛋白；2）SR蛋白调控大脑脂代谢的分子细胞机制，包括脂类在胶质细胞合成、分泌和转运以及神经元的吸收和利用等；3）SR蛋白通过调控脂代谢影响神经元突触结构和功能，Aβ代谢以及AD病理进程的神经生物学机制。基于大脑脂代谢的特性，阐明SR蛋白在神经元和胶质细胞中对脂代谢调控的异同，深入理解神经元和胶质细胞中SR蛋白的调控网络，揭示SR蛋白通过调控脂代谢参与AD病理过程的机制，最终为AD提供全新的治疗方案和药物靶标。

哺乳动物基因组中有大量的RNA结合蛋白基因,而且在大脑中特异性表达。RNA结合蛋白参与突触可塑性的调控，但是其在大脑衰老以及阿尔茨海默病中的作用并不清楚。在本项目的研究中，１）发现胶质细胞来源的ApoE通过其携带的miRNA调控神经元脂代谢和学习记忆，并参与阿尔茨海默病病理进程。ApoE介导的神经元的代谢和表观遗传调控表现为明显的亚型特异性，ApoE4调控神经元胆固醇代谢和表观遗传的能力显著弱于ApoE3，诠释了ApoE4是如何参与阿尔茨海默病的病理进程的。该成果发表在Neuron上。２）发现了一个RNA结合蛋白hnRNP DL以及其如何通过调控RNA剪接过程参与调控大脑衰老以及阿尔茨海默病进程，为进一步理解衰老的大脑的分子机制以及衰老相关的神经退行性疾病的发病机制提供了重要线索。该研究结果发表在Molecular Neurodegeneration上。３）揭示了大脑PFC区的SR蛋白SFRS11通过调控ApoE/LRP8介导的JNK信号通路影响神经元和胶质细胞之间的通讯，从而调节衰老和神经退行改变相关的认知障碍，为不同物种之间的学习记忆等复杂行为差异提供了一种全新的表观遗传调控机制。同时也为理解非编码RNA介导的表观遗传调控在衰老尤其是脑衰老向神经退行改变转变过程中的作用机制提供了重要线索。该成果发表在Cell Reports上。4）同时受综述杂志Trends in Neurosciences的邀请，撰写了一篇综述文章，围绕大脑中不同类型细胞的脂代谢过程，揭示了神经元、星形胶质细胞、小胶质细胞和寡突胶质细胞的脂代谢过程在大脑衰老和阿尔茨海默病病理过程中特异性的改变，并导致认知障碍，同时对病理进程也有影响，为理解衰老及阿尔茨海默病的病理机制提供了重要线索。综上，这些研究都阐明了RNA结合蛋白在大脑衰老以及神经退行性改变过程中的作用机制，并为神经退行性疾病的治疗提供了新靶标。