Fahr综合症相关基因Mea6影响小脑发育和运动行为的机制研究

Fahr综合症是一种神经系统罕见病，主要表现为运动功能异常、语言功能退化和癫痫发作等。Fahr综合症的分子遗传学研究很有限，对其治疗带来了很大的困扰。临床证据显示脑膜瘤表达抗原6（Mea6）突变可能与Fahr综合症相关：患者表现出不稳定的步态和癫痫发作，但不清楚Mea6与运动障碍之间的关系。申请人前期工作发现Mea6对浦肯野细胞和颗粒细胞的发育和功能有不同的调节作用。同时，Mea6可能选择性地影响小脑发育相关分子的功能。申请人将继续利用全细胞膜片钳记录、药理学、分子生物学、细胞生物学、行为研究和基因敲除小鼠等技术，研究：1）Mea6缺失如何影响小脑发育从而导致运动功能异常？2）Mea6缺失如何影响小脑发育相关分子的功能？3）细胞特异性表达Mea6能否挽救Mea6缺失动物的表型？研究成果将推动对Fahr综合症运动功能紊乱机制的理解，为治疗Fahr综合症提供理论基础。

Fahr's syndrome is a rare neurological disorder characterized by motor dysfunction, language deterioration and seizures. The molecular genetics of Fahr's syndrome is very limited, which brings great troubles to its treatment. Clinical evidence suggests that the mutation of meningioma expression antigen 6 (Mea6) may be associated with Fahr's syndrome: patients exhibit unstable gait and seizures, but the relationship between Mea6 and motor disorders is unclear. Our preliminary work found that Mea6 had different regulatory effects on the development and function of Purkinje cells and granule cells. Meanwhile, Mea6 may selectively affect the function of cerebellar development-related molecules. The applicant will continue to use whole-cell patch clamp recording, pharmacology, molecular biology, cell biology, behavioral research and gene knockout mice to study: 1) How does the deletion of Mea6 affect cerebellar development and lead to motor dysfunction? 2) How does the deletion of Mea6 affect the function of cerebellar development-related molecules? 3) Can cell-specific expression of Mea6 rescue the phenotype of Mea6-deficient animals? The research results will promote the understanding of the mechanism of motor dysfunction in Fahr's syndrome and provide a theoretical basis for the treatment of Fahr's syndrome.