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首页> 外文期刊>The European Journal of Neuroscience >Altered apoptotic responses in neurons lacking RhoB GTPase.
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Altered apoptotic responses in neurons lacking RhoB GTPase.

机译：缺乏RhoB GTPase的神经元的凋亡反应发生改变。

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摘要

Caspase 3 activation has been linked to the acute neurotoxic effects of central nervous system damage, as in traumatic brain injury or cerebral ischaemia, and also to the early events leading to long-term neurodegeneration, as in Alzheimer's disease. However, the precise mechanisms activating caspase 3 in neuronal injury are unclear. RhoB is a member of the Rho GTPase family that is dramatically induced by cerebral ischaemia or neurotrauma, both in preclinical models and clinically. In the current study, we tested the hypothesis that RhoB might directly modulate caspase 3 activity and apoptotic or necrotic responses in neurons. Over-expression of RhoB in the NG108-15 neuronal cell line or in cultured corticohippocampal neurons elevated caspase 3 activity without inducing overt toxicity. Cultured corticohippocampal neurons from RhoB knockout mice did not show any differences in sensitivity to a necrotic stimulus - acute calcium ionophore exposure - compared with neurons from wild-type mice. However, corticohippocampal neurons lacking RhoB exhibited a reduction in the degree of DNA fragmentation and caspase 3 activation induced by the apoptotic agent staurosporine, in parallel with increased neuronal survival. Staurosporine induction of caspase 9 activity was also suppressed. RhoB knockout mice showed reduced basal levels of caspase 3 activity in the adult brain. These data directly implicate neuronal RhoB in caspase 3 activation and the initial stages of programmed cell death, and suggest that RhoB may represent an attractive target for therapeutic intervention in conditions involving elevated caspase 3 activity in the central nervous system.
机译：Caspase 3活化与创伤性脑损伤或脑缺血中的中枢神经系统损害的急性神经毒性作用有关，还与阿尔茨海默氏病中导致长期神经变性的早期事件有关。但是，尚不清楚激活caspase 3在神经元损伤中的确切机制。 RhoB是Rho GTPase家族的成员，无论是在临床前模型还是在临床上，RhoB都会被脑缺血或神经创伤严重诱导。在当前的研究中，我们测试了RhoB可能直接调节神经元中caspase 3活性以及凋亡或坏死反应的假设。 RhoB在NG108-15神经元细胞系或培养的皮质海马神经元中的过表达提高了caspase 3的活性，却没有引起明显的毒性。与野生型小鼠的神经元相比，RhoB基因敲除小鼠的培养的皮质海马神经元对坏死刺激的敏感性（急性钙离子载体暴露）没有表现出任何差异。然而，缺乏RhoB的皮质海马神经元显示出由凋亡剂星形孢菌素诱导的DNA片段化和胱天蛋白酶3活化程度的降低，同时神经元存活增加。星形孢菌素诱导的胱天蛋白酶9活性也被抑制。 RhoB基因敲除小鼠显示成年脑中caspase 3活性的基础水平降低。这些数据直接暗示神经元RhoB在caspase 3激活和程序性细胞死亡的初期，并暗示RhoB可能代表在涉及中枢神经系统caspase 3活性升高的疾病中进行治疗性干预的有吸引力的靶标。

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