Mutant TDP-43 in Astrocytes Kills Motor Neurons in Rats through Neurotoxic Gain and Neuroprotective Loss in Astrocytes

Mutation in TDP-43 is causative to amyotrophic lateral sclerosis (ALS). TDP-43 is a multifunctional ribonucleoprotein and is reproted to regulate thousands of genes in neurons, but how astrocytes contribute to TDP-43 pathogenesis is not known. This study examined how mutant TDP-43 in astrocytes kills motor neurons and causes ALS phenotypes. Primary astrocytes were isolated from transgenic rats expressing mutant TDP-43 or from control rats without mutant TDP-43 expression. Cultured astrocytes were induced to express mutant human TDP-43 and their gene expression profiles were determined by microarray assays. Microarray analysis revealed that hundreds of genes were altered in astrocytes in response to mutant TDP-43 expression.TDP-43基因突变可导致肌萎缩侧索硬化症（amyotrophic lateral sclerosis, ALS）。TDP-43是一种多功能核糖核蛋白（ribonucleoprotein），据报道可调控神经元内数千个基因的表达，但星形胶质细胞（astrocytes）如何参与TDP-43的致病机制目前仍不明确。本研究探讨了星形胶质细胞中突变型TDP-43如何杀伤运动神经元并引发ALS表型。研究人员从表达突变型TDP-43的转基因大鼠，以及不表达突变型TDP-43的对照大鼠中分离原代星形胶质细胞。对培养的星形胶质细胞进行诱导，使其表达突变型人源TDP-43，并通过微阵列（microarray）检测其基因表达谱。微阵列分析结果显示，星形胶质细胞中数百个基因的表达会因突变型TDP-43的表达而发生改变。