Mutant superoxide dismutase 1 causes motor neuron degeneration independent of cyclin-dependent kinase 5 activation by p35 or p25.
Mutant superoxide dismutase 1 causes motor neuron degeneration independent of cyclin-dependent kinase 5 activation by p35 or p25.
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突变的超氧化物歧化酶 1 会导致运动神经元变性，与 p35 或 p25 激活细胞周期蛋白依赖性激酶 5 无关。
DOI：
10.1046/j.1471-4159.2003.02256.x
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发表时间：
2004
影响因子：
4.7
通讯作者：
Kulkarni,AshokB
中科院分区：
文献类型：
--
作者：
Takahashi,Satoru;Kulkarni,AshokB
肌萎缩侧索硬化症（ALS）是一种神经退行性疾病，其特征是大脑和脊髓中运动神经元的选择性丧失。谷氨酸介导的神经毒性被认为通过细胞内钙依赖性信号级联在神经元死亡中发挥作用。细胞周期蛋白依赖性激酶 5 (Cdk5) 被认为是钙依赖性介质之一，可能导致这种疾病中观察到的神经元死亡。 Cdk5 在神经元中通过与其激活剂 p35 或 p39 结合而被激活。钙激活蛋白酶钙蛋白酶将 p35 裂解为其截短产物 p25，最终导致细胞错误定位并延长 Cdk5 的激活时间。这种失调的 Cdk5 会诱导细胞骨架破坏和细胞凋亡。为了检查抑制钙蛋白酶介导的 p35 向 p25 的转化是否可以延缓 ALS 的疾病进展，我们生成了双转基因小鼠，其中 ALS 连接的突变体铜/锌超氧化物歧化酶 1 (SOD1G93A) 在 p35 缺失的背景中表达。 p35的缺失既不影响突变型SOD1小鼠运动神经元疾病的发生和进展，也不改善这些小鼠的病理损伤。我们的结果提供了直接证据，表明突变型 SOD1 小鼠运动神经元疾病的发病机制与 p35 或 p25 激活 Cdk5 无关。
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective loss of motor neurons in the brain and spinal cord. Neurotoxicity mediated by glutamate is thought to play a role in the neuronal death through intracellular calcium‐dependent signaling cascades. Cyclin‐dependent kinase 5 (Cdk5) has been proposed as one of the calcium‐dependent mediators that may cause neuronal death observed in this disease. Cdk5 is activated in neurons by the association with its activators, p35 or p39. The calcium‐activated protease calpain cleaves p35 to its truncated product, p25, which eventually causes the cellular mislocalization and prolonged activation of Cdk5. This deregulated Cdk5 induces cytoskeletal disruption and apoptosis. To examine whether inhibition of the calpain‐mediated conversion of p35 to p25 can delay the disease progression of ALS, we generated double transgenic mice in which ALS‐linked mutant copper/zinc superoxide dismutase 1 (SOD1G93A) was expressed in a p35‐null background. The absence of p35 neither affected the onset and progression of motor neuron disease in the mutant SOD1 mice nor ameliorated the pathological lesions in these mice. Our results provide direct evidence that the pathogenesis of motor neuron disease in the mutant SOD1 mice is independent of the Cdk5 activation by p35 or p25.