SIRT2/ABAD介导的神经元线粒体质量控制对认知功能的影响及机制

认知功能障碍是多种神经疾病的共同临床症状。线粒体功能障碍可导致神经元受损并和多种认知障碍相关的神经退行性疾病相关，线粒体干预防治是目前的研究热点和前沿。我们前期研究和近年文献显示SIRT2活性抑制在多种神经退行性疾病中缓解疾病进程，提示可能有治疗这类疾病的共用通路，但机制不明。申请人前期研究发现SIRT2过表达导致成年小鼠的认知功能障碍和线粒体功能异常，SIRT2可能和多种线粒体蛋白相互作用。进一步通过生信分析和预实验锁定了线粒体蛋白ABAD，且ABAD干扰表现出与SIRT2过表达类似的线粒体功能障碍，因此提出SIRT2通过调控ABAD影响线粒体质量控制从而影响神经元活性贡献于认知障碍的科学假说。本课题拟在前期研究探索的基础上从动物水平、细胞水平和分子水平系统验证我们的科学假说。课题通过探究SIRT2对认知功能的影响和机制，为以认知障碍为临床症状的相关神经疾病探寻共同的病理机制和治疗靶点。

Cognitive impairment is a common clinical symptom of many neurological diseases. Mitochondrial dysfunction mediated neuronal damage and is associated with a variety of neurodegenerative diseases combined with cognitive impairment. Mitochondrial intervention is a promising prevention and treatment target for such diseases. In the previous period, our studies and others have shown that SIRT2 inhibition can alleviate the disease process in various neurodegenerative diseases, suggesting that there is a common mechanism for treating such diseases, which remains unclear. Recently, we found that SIRT2 overexpression can lead to cognitive impairment and mitochondrial dysfunction in normal adult mice. Further study found that SIRT2 may interact with various mitochondrial proteins, and a mitochondrial protein ABAD was identified by bioinformatics analysis and pre-experiment. ABAD intervention has a similar effect to SIRT2 overexpression. Therefore, the applicant proposed that SIRT2 could contribute to cognitive impairment by regulating ABAD, affecting mitochondrial quality control, and further affecting neuronal activity. This project intends to systematically test our hypothesis in vivo and in vitro and give the molecular mechanism underling that. This project aims to explore the influence and mechanism of SIRT2 on cognitive function and provide a new light on understanding the common pathological mechanism of related neurological diseases with cognitive impairment as clinical symptoms.