C9ORF72基因非编码区GGGGCC重复扩增是肌萎缩性脊髓侧索硬化症(ALS)和额颞叶痴呆(FTD)最常见的遗传病因。我们已证实，GGGGCC重复扩增序列(r(GGGGCC)exp)募集Purα并介导神经细胞毒性，但具体功能与机制不清。预实验示r(GGGGCC)exp导致Purα分布异常，NF运输障碍，MAP2过磷酸化。已知Purα及其相关蛋白可调节神经元发育和物质运输。据此推测，r(GGGGCC)exp导致Purα及其相关蛋白表达、分布和活性异常，从而介导神经元毒性。本项目拟利用运动神经元模型和大鼠脊髓前角微量注射慢病毒模型，证实r(GGGGCC)exp对神经元的毒性作用；明确r(GGGGCC)exp对Purα及其相关蛋白表达、分布和活性的影响；探讨Purα不同表达水平对r(GGGGCC)exp介导的神经元毒性的影响。本项目将为以Purα为靶点的ALS/FTD的治疗提供理论依据和线索。

The expansion of GGGGCC repeats in the non-coding region of C9ORF72 gene has been shown to be the most common genetic cause of Amyotrophic lateral sclerosis (ALS) and Frontotemporal dementia (FTD). We have confirmed that expanded GGGGCC repeats (r(GGGGCC)exp) mediated neurotoxicity through sequestration of Purα. However, the function and mechanism of Purα in expanded GGGGCC repeats-mediated neuronal toxicity is still unknown. Our preliminary data indicated that r(GGGGCC)exp disturbed normal intracellular distribution of Purα and neurite transportation of neurofilament, and caused hyperphosphorylation of MAP2. It is known that Purα and its associated proteins play key roles in neuron development and neurite transportation. So we hypothesis that r(GGGGCC)exp may induce neuronal toxicity by disturbing the expression, the distribution and the activity of Purα and its associated proteins. By using the models of motor neuron and spinal anterior horn lentiviral-microinjected rats, this project intends to confirm the neuronal toxicity induced by r(GGGGCC)exp, to clarify the effect of r(GGGGCC)exp on the expression, distribution and activity of Purα and its associated proteins, and to explore the impact of different Purα levels in r(GGGGCC)exp-mediated neuronal toxicity. The project will provide a theoretical basis and clues for ALS/FTD therapy targeting Purα.