Sison Samantha L, Patitucci Teresa N, Seminary Emily R, Villalon Eric, Lorson Christian L, Ebert Allison D
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, 53226 WI, USA.
Department of Veterinary Pathobiology, Bond Life Sciences Center, University of Missouri, Columbia, 65211 MO, USA.
Hum Mol Genet. 2017 Sep 1;26(17):3409-3420. doi: 10.1093/hmg/ddx230.
Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, is caused by the loss of the survival motor neuron-1 (SMN1) gene, which leads to motor neuron loss, muscle atrophy, respiratory distress, and death. Motor neurons exhibit the most profound loss, but the mechanisms underlying disease pathogenesis are not fully understood. Recent evidence suggests that motor neuron extrinsic influences, such as those arising from astrocytes, contribute to motor neuron malfunction and loss. Here we investigated both loss-of-function and toxic gain-of-function astrocyte mechanisms that could play a role in SMA pathology. We had previously found that glial derived neurotrophic factor (GDNF) is reduced in SMA astrocytes. However, reduced GDNF expression does not play a major role in SMA pathology as viral-mediated GDNF re-expression did not improve astrocyte function or motor neuron loss. In contrast, we found that SMA astrocytes increased microRNA (miR) production and secretion compared to control astrocytes, suggesting potential toxic gain-of-function properties. Specifically, we found that miR-146a was significantly upregulated in SMA induced pluripotent stem cell (iPSC)-derived astrocytes and SMNΔ7 mouse spinal cord. Moreover, increased miR-146a was sufficient to induce motor neuron loss in vitro, whereas miR-146a inhibition prevented SMA astrocyte-induced motor neuron loss. Together, these data indicate that altered astrocyte production of miR-146a may be a contributing factor in astrocyte-mediated SMA pathology.
脊髓性肌萎缩症（SMA）是导致婴儿死亡的主要遗传原因，由生存运动神经元1（SMN1）基因缺失引起，可导致运动神经元丧失、肌肉萎缩、呼吸窘迫和死亡。运动神经元损失最为严重，但其发病机制尚未完全明确。近期证据表明，运动神经元的外在影响因素，如星形胶质细胞产生的影响，会导致运动神经元功能异常和丧失。在此，我们研究了功能丧失和功能毒性增加的星形胶质细胞机制，这些机制可能在SMA病理学中发挥作用。我们之前发现，SMA星形胶质细胞中的胶质细胞源性神经营养因子（GDNF）减少。然而，GDNF表达降低在SMA病理学中并不起主要作用，因为病毒介导的GDNF重新表达并未改善星形胶质细胞功能或运动神经元丧失。相比之下，我们发现与对照星形胶质细胞相比，SMA星形胶质细胞增加了微小RNA（miR）的产生和分泌，提示可能具有功能毒性增加的特性。具体而言，我们发现miR-146a在SMA诱导多能干细胞（iPSC）衍生的星形胶质细胞和SMNΔ7小鼠脊髓中显著上调。此外，miR-146a增加足以在体外诱导运动神经元丧失，而抑制miR-146a可防止SMA星形胶质细胞诱导的运动神经元丧失。总之，这些数据表明，星形胶质细胞miR-146a产生改变可能是星形胶质细胞介导的SMA病理学的一个促成因素。
