肌萎缩侧索硬化症（ALS）是一类严重的致死性神经退行性疾病，其核心病理特征是运动神经元死亡；而调控细胞结构和功能的关键基因突变，是引起神经元结构和功能异常并导致神经元死亡的重要原因。本项目申请人长期致力于ALS的发病机制，尤其是寻找ALS新的致病基因及突变位点的相关研究。在前期研究中，我们在ALS患者中初步筛查发现内质网-线粒体偶联蛋白PDZD8的N端跨膜结构域发生错义突变（c. 20T>C; p. I7T）；进一步功能验证发现，该突变会引起PDZD8内质网定位异常和蛋白稳定性降低。据此我们提出，ALS中新发现的PDZD8错义突变，可能通过破坏其内质网定位及蛋白稳定性，进而影响内质网-线粒体互作，引起神经元死亡和ALS疾病发生。本项目拟利用临床样本、细胞及动物模型，探究PDZD8错义突变对其蛋白功能的影响，阐明该突变引起ALS发病的分子机制，为ALS的早期诊断和治疗提供新的思路和分子靶点。

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, with motor neuron death as its pathological characteristic. It's well accepted with genetic mutations of crucial genes regulating cell structural and functional homeostasis are direct reasons for neuronal dysfunctions and death. Our team has long been committed to study the pathogenesis of ALS, especially in search of novel genes and mutations associated with ALS. In previous studies, we discovered a novel missense mutation (c. 20T>C ; p. I7T) at the N-terminal of transmembrane domain of PDZD8, the key protein mediating endoplasmic reticulum (ER)-mitochondrial tethering. Further studies revealed that this mutation impairs the ER-localization of PDZD8 and decreases its protein stability. Based on these findings, we propose that this novel missense mutation of PDZD8 may disrupt protein subcellular localization, promote protein degradation, impair ER-mitochondrial interaction, lead to neuronal death and ALS development. This project intends to combine clinical samples, cultured cells and animal models to explore how PDZD8 missense mutation causes ALS, and provide new insights and molecular targets for early diagnosis and clinical interventions of ALS.