腓骨肌萎缩症中遗传与环境因素互作的分子机制及潜在治疗方案

Emerging evidence has begun to reveal that neurological diseases may arise from a combination of genetic risk factors and environmental influences. Charcot-Marie-Tooth (CMT) diseases are the most common hereditary peripheral neuropathies that are characterized by progressive motor/sensory dysfunction. A subtype of the diseases—CMT2D—is caused by dominant mutations in GARS gene, encoding the ubiquitously expressed enzyme glycyl-tRNA synthetase (GlyRS). The PI’s recent studies have revealed that CMT2D mutations alter the conformation of GlyRS, enabling mutant GlyRS to bind Nrp1. This aberrant interaction antagonizes the binding of vascular endothelial growth factor (VEGF) to Nrp1, thereby contributing to motor defects in CMT2D. These findings link the CMT2D pathology to the neomorphic binding activity of mutant GlyRS that antagonizes the VEGF/Nrp1 interaction. However, in many cases, CMT patients carry the same gene mutation but may develop substantial clinical variability in disease expression. Recent clinical studies have revealed that environmental factors such as vitamin D deficiency predispose to the development of peripheral neuropathy symptoms. However it remains unclear whether these genetic and environmental pathways are integrated into a hierarchical signaling network that contributes to peripheral nerve pathology. The overall goal of this proposal is to characterize the signal integration of Vitamin D and GARS pathways in CMT2D pathogenesis. The proposed experiments are expected to reveal the key molecular link that integrates genetic and environmental factors in CMT2D, and to identify the actionable targets for treating CMT2D.

大部分的神经系统疾病都是由遗传因素和环境因素共同作用的结果。腓骨肌萎缩症（Charcot-Marie-Tooth Neuropathy，CMT）是最常见的遗传性周围神经系统疾病之一，其中CMT2D亚型是由GARS基因上的显性遗传突变所引起的，该基因编码甘氨酰-tRNA合成酶。本项目的前期研究发现：GARS基因上的致病突变会导致其蛋白质构象发生改变,使得突变蛋白获得异常的结合活性，干扰VEGF/Nrp1信号通路，从而导致运动神经病变。事实上，临床上有大量的CMT病例，患者携带相同的基因突变, 却在临床症状的严重程度上表现出很大的差异性。大量证据表明维生素D缺乏等环境因素很可能在这个过程中扮演了重要角色。本项研究将以CMT2D为切入点，针对维生素D介导的环境因素和GARS基因突变所介导的遗传因素之间的分子联系和信号整合展开研究，并探索维生素D信号通路作为治疗CMT药物靶点的潜力。