Blood-spinal cord barrier (BSCB) disruption is thought to contribute to motoneuron (MN) loss in amyotrophic lateral sclerosis (ALS). It is currently unclear whether impairment of the BSCB is the cause or consequence of MN dysfunction and whether its restoration may be directly beneficial. We revealed that SOD1 ^G93A , FUS^ΔNLS , TDP43 ^G298S , and Tbk1 ^+/- ALS mouse models commonly shared alterations in the BSCB, unrelated to motoneuron loss. We exploit PSAM/PSEM chemogenetics in SOD1 ^G93A mice to demonstrate that the BSCB is rescued by increased MN firing, whereas inactivation worsens it. Moreover, we use DREADD chemogenetics, alone or in multiplexed form, to show that activation of Gi signaling in astrocytes restores BSCB integrity, independently of MN firing, with no effect on MN disease markers and dissociating them from BSCB disruption. We show that astrocytic levels of the BSCB stabilizers Wnt7a and Wnt5a are decreased in SOD1 ^G93A mice and strongly enhanced by Gi signaling, although further decreased by MN inactivation. Thus, we demonstrate that BSCB impairment follows MN dysfunction in ALS pathogenesis but can be reversed by Gi-induced expression of astrocytic Wnt5a/7a.

中文翻译：

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星形胶质细胞和运动神经元中的多重化学遗传学可恢复ALS中的血脊髓屏障。

人们认为，血脊髓屏障（BSCB）的破坏会导致肌萎缩性侧索硬化症（ALS）中的运动神经元（MN）丢失。目前尚不清楚BSCB的损伤是否是MN功能障碍的原因或后果，其恢复是否可能直接有益。我们发现，SOD1 ^G93A，FUS ^{Δ NLS}，TDP43 ^G298S和TBK1 ^+/- ALS小鼠模型常用共享的BSCB的变化，无关的运动神经元的损失。我们利用SOD1 ^G93A中的PSAM / PSEM化学^成因 小鼠证明BSCB可通过增加MN射击而获救，而失活会使它恶化。此外，我们单独或以多重形式使用DREADD化学遗传学方法，以显示星形胶质细胞中Gi信号的激活可恢复BSCB完整性，而与MN激发无关，对MN疾病标志物没有影响，也不会使它们脱离BSCB破坏。我们显示，在SOD1 ^G93A小鼠中BSCB稳定剂Wnt7a和Wnt5a的星形细胞水平降低，并且通过Gi信号强烈增强，尽管通过MN灭活进一步降低。因此，我们证明BSCB损伤在ALS发病机制中遵循MN功能障碍，但可以由Gi诱导的星形细胞Wnt5a / 7a表达逆转。