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人类中枢神经系统神经元的编程神经元退化是由NAD代谢的变化驱动的

Markus Brüll¹, Selina Multrus¹, Michael Schäfer¹

¹In vitro Toxicology and Biomedicine, Dept. inaugurated by the Doerenkamp-Zbinden foundation, University of Konstanz, 78457, Konstanz, Germany.

Cell death & disease

|January 17, 2025

概括

中枢神经系统中的神经元退化是由NAD+代谢和SARM1.1.酶控制的. 补充NAD+或抑制SARM1可以防止这一过程,提供新的治疗策略.

科学领域:

神经科学是一个神经科学.
细胞生物学细胞生物学
生物化学生物化学

背景情况:

神经衰变 (ND) 是神经退行性疾病的标志,但其在中枢神经系统 (CNS) 的调节尚未完全理解.
在外周神经系统 (PNS) 上进行的先前研究表明,NAD+代谢和SARM1与轴切术诱导的退化有关.

研究的目的:

为了研究神经元退化的新陈代谢控制在人类中枢神经系统神经元 axotomy后.
探索NAD+代谢和SARM1在中枢神经系统神经元退化中的作用.

主要方法:

使用从人类中脑神经元中获得的3D LUHMES培养物建立了中枢神经系统轴切模型.
研究了轴切术对NAD+水平,NMNAT2表达和线粒体呼吸的影响.
利用SARM1倒置,主导-负SARM1表达,NAD+补充和WLD的蛋白质来评估它们对ND的影响.
排除了ferroptosis,necroptosis和caspase依赖的apoptosis作为神经元损失的机制.

主要成果:

轴切导致NMNAT2的快速丧失和中枢神经系统神经元中的NAD+的枯竭.
隔离的神经元保持ATP水平和线粒体呼吸至少6小时.
抑制SARM1显著延迟神经元退化.
调节NAD+代谢并补充NAD+减弱的神经元退化.
通过稳定NAD+水平,WLD的蛋白质保护神经元.

结论:

中枢神经系统类型的神经元退化与神经元代谢密切相关,特别是NAD+水平.
在中枢神经系统中,SARM1充当了这一过程的关键调节者或执行者.
准NAD+代谢和SARM1为神经退行性疾病提供了有前途的治疗策略.

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