ALS 诱导多能干细胞运动神经元中的异常轴突起始段可塑性和内在兴奋性。

Aberrant axon initial segment plasticity and intrinsic excitability of ALS hiPSC motor neurons.

机构信息

Centre for Gene Therapy & Regenerative Medicine, Kings College London, London SE1 9RT, UK; Centre for Developmental Neurobiology, Kings College London, London SE1 1UL, UK; UCL Queen Square Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK.

Centre for Gene Therapy & Regenerative Medicine, Kings College London, London SE1 9RT, UK; Centre for Developmental Neurobiology, Kings College London, London SE1 1UL, UK; Centre for Craniofacial & Regenerative Biology, King's College London, London SE1 9RT, UK.

出版信息

Cell Rep. 2023 Dec 26;42(12):113509. doi: 10.1016/j.celrep.2023.113509. Epub 2023 Nov 28.

DOI:10.1016/j.celrep.2023.113509

PMID:38019651

Abstract

Dysregulated neuronal excitability is a hallmark of amyotrophic lateral sclerosis (ALS). We sought to investigate how functional changes to the axon initial segment (AIS), the site of action potential generation, could impact neuronal excitability in ALS human induced pluripotent stem cell (hiPSC) motor neurons. We find that early TDP-43 and C9orf72 hiPSC motor neurons show an increase in the length of the AIS and impaired activity-dependent AIS plasticity that is linked to abnormal homeostatic regulation of neuronal activity and intrinsic hyperexcitability. In turn, these hyperactive neurons drive increased spontaneous myofiber contractions of in vitro hiPSC motor units. In contrast, late hiPSC and postmortem ALS motor neurons show AIS shortening, and hiPSC motor neurons progress to hypoexcitability. At a molecular level, aberrant expression of the AIS master scaffolding protein ankyrin-G and AIS-specific voltage-gated sodium channels mirror these dynamic changes in AIS function and excitability. Our results point toward the AIS as an important site of dysfunction in ALS motor neurons.

摘要

神经元兴奋性失调是肌萎缩侧索硬化症（ALS）的一个标志。我们试图研究轴突起始段（AIS）的功能变化如何影响 ALS 人类诱导多能干细胞（hiPSC）运动神经元的兴奋性。我们发现，早期 TDP-43 和 C9orf72 hiPSC 运动神经元的 AIS 长度增加，活性依赖性 AIS 可塑性受损，这与神经元活动的异常稳态调节和内在的过度兴奋性有关。反过来，这些过度活跃的神经元导致体外 hiPSC 运动单位中自发性肌纤维收缩增加。相比之下，晚期 hiPSC 和尸检 ALS 运动神经元表现出 AIS 缩短，而 hiPSC 运动神经元进展为兴奋性降低。在分子水平上，AIS 主支架蛋白锚蛋白-G 和 AIS 特异性电压门控钠通道的异常表达反映了 AIS 功能和兴奋性的这些动态变化。我们的研究结果表明 AIS 是 ALS 运动神经元功能障碍的一个重要部位。