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RIPK1通过促进ALS的炎症和亡来调解轴突退化

Yasushi Ito¹, Dimitry Ofengeim¹, Ayaz Najafov¹

¹Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.

Science (New York, N.Y.)

|August 6, 2016

概括

中枢神经系统 (CNS) 中的光氨尿素 (OPTN) 损失通过 RIPK1 信号触发了渐进式轴突退化,这是肌缩侧面硬化症 (ALS) 病理的一个关键因素. 抑制RIPK1激酶可能为ALS和其他神经退行性疾病提供神经保护策略.

科学领域:

神经科学
分子生物学
遗传学

背景情况:

选择性尿素 (OPTN) 基因突变与肌缩侧面硬化症 (ALS) 有关.
在中枢神经系统 (CNS) 内的精确功能及其对ALS病变的贡献仍然不完全理解.
对神经退行性疾病相关的神经炎症和细胞死亡途径涉及受体相互作用激酶1 (RIPK1) 信号.

研究的目的:

阐明optineurin在中枢神经系统中调节RIPK1依赖的信号传递中的作用.
对中枢神经系统完整性和轴突健康的影响进行调查.
确定RIPK1和相关的亡途径组件在ALS相关的轴突退化中的参与.

主要方法:

利用分子生物学技术研究了optineurin与RIPK1的相互作用.
在体内研究了氨酸缺乏对中枢神经系统髓化和轴突完整性的影响.
在ALS小鼠模型和人类患者样本中检查了RIPK1,RIPK3和MLKL的表达和激活.

主要成果:

通过调节RIPK1的循环,发现optineurin可以抑制RIPK1依赖的信号传递.
失去了光尿素导致中枢神经系统的逐渐失髓化和轴突退化.
在中枢神经系统中,因失去了光蛋白激素而激活了涉及RIPK1,RIPK3和MLKL的死亡途径.
在SOD1 ((G93A)) 转基因小鼠和人类ALS患者的组织中,RIPK1和RIPK3介导的轴突病理普遍存在.

结论:

在中枢神经系统中抑制RIPK1介导的死细胞信号传递方面,光氨酸起着至关重要的作用.
在ALS中,RIPK1和RIPK3是渐进性轴突退化的关键媒介.
向RIPK1激酶活性为ALS和其他神经退行性疾病中保护轴突提供了潜在的治疗途径.

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