线粒体锚定蛋白连接酶MAPL介导的线粒体分裂在阿尔茨海默病中的分子机理研究

Neuronal mitochondrial dysfunction is caused by abnormal mitochondrial dynamics, which is one of the earliest and prominent pathological features in Alzheimer’s disease (AD). However, the underlying molecular mechanisms of mitochondrial dynamic disequilibrium and crucial components involved in this process during the early stage of AD need to be explored in detail. Mitochondrial anchored protein ligase (MAPL) is a small ubiquitin-like modifier (SUMO) E3 ligase, which locates on mitochondrial outer membrane and plays major roles in several diseases via targeting mitochondrial fission. The current study found that the expression of MAPL is enhanced in neuronal cells under AD condition, but its functions in neuronal mitochondrial fission and AD pathological process remains largely unknown. In the proposed study, we will explore the cellular and molecular functions of MAPL in mitochondrial fission during the pathological process of AD using various molecular techniques including mitochondria labeling, synaptic structure detection combined with animal behavior methods, and bioinformatics tools combined with molecular interaction detection assays such as CHIP, RIP, or RNA pull-down methods. The successful completion of this study will provide a new molecular and experimental basis in searching of potential drug targets and early biomarkers for the diagnosis and therapy of AD.

线粒体动态失衡导致的功能障碍是阿尔茨海默病（AD）早期的主要病理特征之一。然而，AD发病早期线粒体动态失衡的关键调控因子及其分子机理还有待进一步研究。线粒体锚定蛋白连接酶（MAPL）是一种位于线粒体外膜上的泛素化/小泛素化E3连接酶，通过调控线粒体分裂参与某些疾病过程。本计划前期结果发现MAPL在AD神经细胞中的表达水平增高，但其在神经元线粒体分裂及AD中的功能及分子机制还尚未清楚。本计划拟在细胞及动物水平上，主要利用线粒体形态观察、突触结构检测结合行为学方法，以及生物信息学预测结合CHIP、RIP、RNA pull-down等分子互作技术探究MAPL与神经元线粒体分裂的关系及其在AD病理进程中的分子机理，揭示AD发病早期线粒体动态失衡的关键调控子，为寻找AD早期新的潜在用药靶点及生物标记物提供实验基础与理论依据。

线粒体动态失衡导致的功能障碍是阿尔茨海默病（AD）早期的主要病理特征之一。然而，AD发病早期线粒体动态失衡的关键调控因子及其分子机理还有待进一步研究。线粒体锚定蛋白连接酶（MAPL）是一种位于线粒体外膜上的泛素化/小泛素化E3连接酶，通过调控线粒体分裂参与某些疾病过程。本计划在细胞及动物水平上，主要利用观察线粒体形态观察、线粒体功能检测、MTT、Western blot、生物信息学预测及RIP等技术探究MAPL与神经元线粒体分裂的关系及其在AD病理进程中的分子机理，揭示AD发病早期线粒体动态失衡的关键调控子，为寻找AD早期新的潜在用药靶点及生物标记物提供实验基础与理论依据。