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神经细胞SEL1L-HRD1 ERAD调节单碳代谢,对于运动功能和生存至关重要

Mauricio Torres¹, You Lu², Brent Pederson²

¹Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.

bioRxiv : the preprint server for biology

|July 16, 2025

概括

神经元SEL1L-HRD1与ER相关的降解 (ERAD) 对单碳代谢和运动功能至关重要. 它在小鼠中的缺乏反映了人类神经发育疾病,揭示了ERAD.

科学领域:

神经科学是一个神经科学.
分子生物学分子生物学
代谢生物化学代谢生物化学

背景情况:

在SEL1L-HRD1 ER相关降解 (ERAD) 复合体中的低形变异与严重的儿科神经综合征有关.
神经元ERAD在生理功能中的确切作用和机制在很大程度上是未知的.

研究的目的:

在体内研究神经元SEL1L-HRD1 ERAD的基本功能.
阐明ERAD相关神经发育障碍背后的分子机制.

主要方法:

产生特定于神经元的Sel1L淘汰赛小鼠 (SynCre).
现型分析包括运动功能评估和生存研究.
多基因分析:单核RNA测序和代谢学.

主要成果:

神经元特异的Cel1L删除导致生长迟缓,严重的运动障碍和早期死亡,模仿人类疾病表型.
尽管有神经元损失,但ER压力很小,这表明ERAD的作用超出了标准蛋白质质量控制范围.
多组组学揭示了单碳新陈代谢的显著失调,包括与综合应激反应 (ISR) 相关的血清素,叶酸和氨酸途径.

结论:

神经细胞SEL1L-HRD1 ERAD对于维持运动功能,活力和单碳代谢至关重要.
这项研究揭示了ERAD在整合ER蛋白质质量控制与神经元中的代谢适应方面发挥的新角色.
这些发现为ERAD相关的神经发育疾病的分子基础提供了关键的见解.

关键词:

在SEL1L-HRD1 ERADAD中.增长减缓增长减缓增长减缓综合应激反应综合应激反应代谢生物组的代谢生物组运动功能障碍运动功能障碍神经元神经元的神经元一个碳代谢的一个碳代谢.过早的死亡率过早的死亡率一个核的RNA-Seqq.

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