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在VAPB相关的ALS中,综合应激反应的融合激活和ER-线粒体脱

Curran Landry¹, James P Costanzo¹, Miguel Mitne-Neto^2,3

¹Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.

EMBO molecular medicine

|August 5, 2025

概括

VAPB P56S突变通过破坏ER-线粒体连接并激活综合应激反应 (ISR) 来损害运动神经元功能. 阻断ISR为这种形式的肌缩侧面硬化症 (ALS) 提供了潜在的治疗策略.

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
遗传学遗传学是一个

背景情况:

囊泡关联膜蛋白关联蛋白-B (VAPB) 是一个内分泌网膜 (ER) 蛋白.
在VAPB中发生的一种特定突变 (P56S) 会导致家族性肌缩侧面硬化症 (ALS).
将VAPB P56S突变与运动神经元 (MN) 退化联系在一起的精确机制尚未完全理解.

研究的目的:

调查VAPB P56S相关的ALS背后的细胞和分子机制.
探索ER-线粒体相互作用和综合应激反应 (ISR) 在疾病发病过程中的作用.
评估ISR抑制作为VAPB P56S ALS.的潜在治疗方法.

主要方法:

使用诱导多能干细胞 (iPSC) 衍生的运动神经元 (MN),表达野生类型 (WT) 或突变P56S VAPB.
评估了神经元激发,ER-线粒体相关膜 (ER MAM),线粒体膜潜力 (MMP) 和ER应激反应.
在患者衍生的iPSC-MN和使用ISRIB测试ISR抑制的验证结果.

主要成果:

VAPB P56S突变减少了神经元发射,并破坏了ER MAMs,导致MMP减少.
VAPB P56S MNs表现出增加的ER应激敏感性,增加的ATF4表达和减少的蛋白质合成.
使用ISRIB的药理抑制在突变和患者衍生的iPSC-MN中拯救了ALS相关的表型.
证明了VAPB P56S突变激活ISR信号通过线粒体功能障碍在人类MNS.

结论:

VAPB P56S突变通过线粒体功能障碍和随后的ISR激活在人类运动神经元中启动ALS病原体.
在VAPB P56S相关的ALS中,ISR调节是一种有前途的治疗策略.
基于ISR通路激活的患者分层可能对未来的临床试验至关重要.

关键词:

这是ALS (性侧面硬化症).ER-MAM (内质网膜线粒体关联膜) 是一种综合应激反应 (ISR) 是一种综合应激反应.神经退行发生神经退行.VAPB ((囊关联膜蛋白关联蛋白B) 是一种

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