2-羟基戊二酸尿症中枢神经损伤致病机制和干预研究

2-hydroxy glutaric aciduria (2-HGA) is a rare autosomal recessive metabolic disorder. This disorder is characterized by injury of central nervous system (CNS) and development of glioma in some L-2-HGA patients. To date, the mechanisms for 2-HGA pathogenesis are largely unknown. It is acknowledged that 2-HG can impair mitochondrial function and eventually cause neurodegeneration. We have previously.shown that 2-HG acts as an oncometabolite and is involved in epigenetic control of gene regulation. Recently, D2hgdh or L2hgdh knockout mice were generated, and we found that the 2-HG levels in these animals are comparable to those in 2-HGA patients. Moreover, like L-2-HGA patients, L2hgdh knockout mice exhibited abnormality in white matter and basal ganglia lesions. In this proposal, we will perform comprehensive analysis of biological phenotypes in D2hgdh or L2hgdh knockout mice. Whether 2-HG is the major neurotoxic metabolite which leads to CNS injury and even promotes tumorigenesis will be investigated. This study will uncover previously unknown molecular regulatory networks which contribute to 2-HGA pathogenesis, and will provide theoretical support and a breakthrough for clinical.diagnosis and treatment of 2-HGA.

2-羟基戊二酸尿症（2-HGA）是一种罕见的常染色体隐性遗传病，由代谢酶2-羟基戊二酸脱氢酶（2-HGDH）或异柠檬酸脱氢酶2（IDH2）突变所致，临床表征为2-羟基戊二酸(2-HG)在病人体液和脑部蓄积、中枢神经系统功能紊乱，少数患者还发生脑肿瘤。已知2-HG调控表观遗传和基因转录，也影响线粒体功能和细胞代谢，但2-HG如何诱发2-HGA中枢神经损伤甚至肿瘤，相关作用机制并不清楚。申请人团队前期研究发现，2-HG分解代谢酶2-HGDH基因敲除导致2-HG在小鼠体内蓄积，L2hgdh基因敲除小鼠还表现出与L-2HGA患者类似的脑白质和基底神经节病变。本项目拟对D/L-2HGDH基因敲除小鼠开展深入的表型分析，剖析2-HG蓄积致病的分子调控网络，降低2-HG水平并干预具有重要细胞生物学功能的2-HG下游靶标，包括表观遗传和线粒体呼吸链，旨在为2-HGA临床诊治提供理论支持和突破口。

本项目以2-羟基戊二酸（2-HG）、衣康酸（ITA）等有机酸为研究对象，探讨细胞代谢对中枢神经损伤的保护机制和潜在干预策略。2-HG和ITA均与α-酮戊二酸（α-KG）结构类似，都能调控表观酶活性和改变细胞表观谱。通过构建不同遗传小鼠模型中，本项目实验结果表明代谢酶2HGDH基因敲除导致2-HG积累、组蛋白甲基化等表观遗传性状改变、脑白质和基底神经节病变，但并不显著影响小鼠中枢神经系统功能及行为学表型。而代谢酶Irg1基因敲除导致ITA在急性脑损伤后的脑组织内不能积累，诱发血脑屏障完整性降低、脑水肿严重以及条件恐惧记忆更差的行为学表型。在细胞层面，Irg1基因敲除小鼠在急性脑损伤后呈现小胶质细胞异常激活的表征，这与ITA在小胶质细胞激活过程中积累，抑制表观酶Tet2活性和调控NF-KB和JAK-STAT通路密切相关。更为重要的是，采用脑室注射ITA的干预手段，能显著改善急性脑损伤后小鼠血脑屏障完整性，缓解脑水肿，并恢复条件恐惧记忆的行为学表型。后续研究将重点关注上述神经炎症反应如何影响小胶质细胞与星形胶质细胞、神经元等不同细胞类型的生物互作，将有助于阐明衣康酸等代谢物发挥中枢神经损伤保护作用的核心分子机制，并寻找有效的代谢干预策略。