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Dysregulation of Rac or Rho elicits death of motor neurons and activation of these GTPases is altered in the G93A mutant hSOD1 mouse model of amyotrophic lateral sclerosis.
Neurobiology of Disease ( IF 6.1 ) Pub Date : 2020-01-10 , DOI: 10.1016/j.nbd.2020.104743
Trisha R Stankiewicz 1 , Claudia Pena 1 , Ron J Bouchard 2 , Daniel A Linseman 3
Affiliation  

Rho GTPases play a central role in neuronal survival; however, the antagonistic relationship between Rac and Rho in the regulation of motor neuron survival remains poorly defined. In the current study, we demonstrate that treatment with NSC23766, a selective inhibitor of the Rac-specific guanine nucleotide exchange factors, Tiam1 and Trio, is sufficient to induce the death of embryonic stem cell (ESC)-derived motor neurons. The mode of cell death is primarily apoptotic and is characterized by caspase-3 activation, de-phosphorylation of ERK5 and AKT, and nuclear translocation of the BH3-only protein Bad. As opposed to the inhibition of Rac, motor neuron cell death is also induced by constitutive activation of Rho, via a mechanism that depends on Rho kinase (ROCK) activity. Investigation of Rac and Rho in the G93A mutant, human Cu, Zn-superoxide dismutase (hSOD1) mouse model of amyotrophic lateral sclerosis (ALS), revealed that active Rac1-GTP is markedly decreased in spinal cord motor neurons of transgenic mice at disease onset and end-stage, when compared to age-matched wild type (WT) littermates. Furthermore, although there is no significant change in active RhoA-GTP, total RhoB displays a striking redistribution from motor neuron nuclei in WT mouse spinal cord to motor neuron axons in end-stage G93A mutant hSOD1 mice. Collectively, these data suggest that the intricate balance between pro-survival Rac signaling and pro-apoptotic Rho/ROCK signaling is critical for motor neuron survival and therefore, disruption in the balance of their activities and/or localization may contribute to the death of motor neurons in ALS.

中文翻译:

Rac或Rho失调引起运动神经元死亡,并且在肌萎缩性侧索硬化症的G93A突变型hSOD1小鼠模型中,这些GTPases的激活发生改变。

Rho GTPases在神经元存活中起着核心作用。然而,Rac和Rho之间在运动神经元存活的调节中的拮抗关系仍然不清楚。在当前的研究中,我们证明用NSC23766(Rac特异性鸟嘌呤核苷酸交换因子Tiam1和Trio的选择性抑制剂)治疗足以诱导胚胎干细胞(ESC)衍生的运动神经元死亡。细胞死亡的模式主要是凋亡的,其特征在于caspase-3激活,ERK5和AKT的去磷酸化以及仅BH3蛋白Bad的核易位。与抑制Rac相反,通过依赖Rho激酶(ROCK)活性的机制,Rho的组成型活化也诱导了运动神经元细胞死亡。研究G93A突变体人Cu中的Rac和Rho 肌萎缩性侧索硬化症(ALS)的Zn超氧化物歧化酶(hSOD1)小鼠模型显示,与年龄匹配的野生型相比,在疾病发作和末期时,转基因小鼠的脊髓运动神经元中活性Rac1-GTP明显降低(WT)同窝仔。此外,尽管活性RhoA-GTP没有明显变化,但总RhoB从WT小鼠脊髓中的运动神经元核到末期G93A突变型hSOD1小鼠中的运动神经元轴突显着重新分布。总体而言,这些数据表明,促存活的Rac信号和促凋亡的Rho / ROCK信号之间的复杂平衡对于运动神经元存活至关重要,因此,其活动和/或定位平衡的破坏可能会导致运动神经元的死亡。 ALS中的神经元。
更新日期:2020-01-11
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