Loss of TDP-43 in astrocytes leads to motor deficits by triggering A1-like reactive phenotype and tri-glial dysfunctions

The majority of patients with amyotrophic lateral sclerosis (ALS) have abnormal TDP-43 aggregates in the nucleus and/or cytosol of their surviving neurons and glia. Although accumulating evidence indicates that astroglial dysfunctions contribute to motor neuron degeneration in ALS, the normal physiological functions of TDP-43 in astrocytes are largely unknown and whether the loss of astroglial TDP-43 contributes to ALS remains to be clarified. Here, we showed that TDP-43 deleted astrocytes showed cell-autonomously enhanced GFAP immunoreactivity without affecting astrocyte or microglia proliferation. At the transcriptomic level, TDP-43 deleted astrocytes resemble the A1-reactive astrocytes and induce microglia to increase C1q expression. These astrocytic changes do not cause the loss of motor neurons in spinal cords or denervation at the neuromuscular junctions. In contrast, there was a selective reduction of mature oligodendrocytes, but not oligodendrocyte precursor cells, suggesting a tri-glial dysfunction mediated by TDP-43-deleted astrocytes. Mice with astroglial TDP-43 deletion developed motor, but not sensory, deficits. Taken together, our results demonstrate that TDP-43 is required to maintain the protective functions of astrocytes relevant to the development of motor deficits in mice. Differential gene expression analysis of spinal cord sections of 3-month old mice with TDP-43 deleted in astrocytes绝大多数肌萎缩侧索硬化症（ALS）患者的存活神经元与胶质细胞的细胞核及/或细胞质中，存在异常的TDP-43聚集物。尽管越来越多的证据表明，星形胶质细胞功能异常参与了ALS的运动神经元退行性变过程，但TDP-43在星形胶质细胞中的正常生理功能仍未完全明确，且星形胶质细胞TDP-43缺失是否参与ALS的发病过程，仍有待进一步阐明。本研究结果显示，TDP-43缺失的星形胶质细胞会以细胞自主性方式增强胶质纤维酸性蛋白（Glial Fibrillary Acidic Protein，GFAP）免疫反应性，且不会影响星形胶质细胞或小胶质细胞的增殖。在转录组层面，TDP-43缺失的星形胶质细胞与A1型反应性星形胶质细胞表型相似，并可诱导小胶质细胞上调C1q的表达。此类星形胶质细胞的变化并不会导致脊髓运动神经元丢失，也不会引发神经肌肉接头处的去神经支配。与之相反，该模型中成熟少突胶质细胞出现选择性减少，但少突胶质前体细胞数量未受影响，这提示TDP-43缺失的星形胶质细胞介导了三胶质细胞功能异常。星形胶质细胞TDP-43缺失的小鼠会出现运动功能缺陷，但无感觉功能异常。综上，本研究结果证实，TDP-43是维持星形胶质细胞保护功能所必需的，这与小鼠运动功能缺陷的发生发展密切相关。对星形胶质细胞TDP-43缺失的3月龄小鼠脊髓切片进行的差异基因表达分析。