Motor neuron degeneration in amyotrophic lateral sclerosis (ALS) caused by mutations in superoxide dismutase 1 (SOD1) is partly non-cell autonomous, involving cellular dysfunction of astrocytes. Whether non-cell autonomous effects occur in other forms of ALS, such as TAR DNA binding protein 43 (TDP-43)-related disease, remains unclear. Here, we characterised the impact of mutant TDP-43 expression on primary astrocytes derived from transgenic TDP-43A315T mice. Mutant TDP-43 astrocytes revealed evidence for TDP-43 pathology, shown by cytoplasmic TDP-43 inclusions and accumulation in insoluble cell fractions which was exacerbated by proteasomal inhibition. L-glutamate uptake, measured using an [3H]D-aspartate assay, was impaired in mutant TDP-43 astrocytes, while ATP accumulation was abnormal, suggesting mutant TDP-43 induced astrocytic dysfunction. Astrocyte activation coupled with spinal and cortical motor neuron loss in transgenic TDP-43A315T mice could imply non-cell autonomous effects of astrocytes in vivo. These data demonstrate mutant TDP-43-mediated cell autonomous effects on astrocytes that may contribute to motor neuron pathology in ALS.

中文翻译：

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TDP-43突变表达触发TDP-43病理和对原代星形胶质细胞的细胞自治作用：对ALS中非细胞自治病理的影响。

由超氧化物歧化酶1（SOD1）突变引起的肌萎缩性侧索硬化症（ALS）中的运动神经元变性是部分非细胞自主性的，涉及星形胶质细胞的细胞功能障碍。尚不清楚非细胞自主效应是否以其他形式的ALS发生，例如与TAR DNA结合蛋白43（TDP-43）相关的疾病。在这里，我们表征了突变型TDP-43表达对源自转基因TDP-43A315T小鼠的原代星形胶质细胞的影响。突变的TDP-43星形胶质细胞揭示了TDP-43病理的证据，其表现为胞质TDP-43内含物和不溶性细胞部分中的积累，这被蛋白酶体抑制所加剧。使用[3H] D-天冬氨酸测定法测定的L-谷氨酸摄取在突变的TDP-43星形胶质细胞中受损，而ATP积累异常，表明突变的TDP-43诱导了星形细胞功能异常。在转基因TDP-43A315T小鼠中，星形胶质细胞的活化与脊柱和皮质运动神经元的丧失相结合，可能暗示了星形胶质细胞在体内的非细胞自主作用。这些数据证明，突变型TDP-43介导的星形胶质细胞自主作用可能促进ALS的运动神经元病理。