适应内网膜蛋白质稳定性可以拯救相关的NMDA受体变体
Pei-Pei Zhang1, Taylor M Benske1, Lucie Y Ahn2
1Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA.
Acta pharmacologica Sinica
|October 6, 2023
概括
小分子BIX增强了与有关的N-甲基-D-酸盐受体 (NMDAR) 变体的表面表达. 这种方法改善了蛋白质折叠和贩运,为NMDAR相关的神经疾病提供了潜在的治疗方法.
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
- 遗传学 遗传学 是一个
背景情况:
- N-甲基-D-酸盐受体 (NMDARs) 对神经元功能至关重要,它们编码基因 (GRIN) 的变异可能导致严重的神经系统疾病.
- 致病性NMDAR变体经常表现出蛋白质错折,组装受损,表面表达减少和功能障碍活动,导致和智力障碍等疾病.
研究的目的:
- 调查GluN2A子单元中与相关的NMDAR变体的蛋白质稳定机制.
- 评估通过使用小分子来调节内质网膜 (ER) 蛋白质稳定酶以恢复NMDAR功能的治疗潜力.
主要方法:
- 利用HEK293T细胞和人类iPSC衍生的神经元来研究与相关的NMDAR变体 (M705V,A727T).
- 给了BIX,一个小分子激活器的HSP70伴侣BiP,以评估其对变体表达和功能的影响.
- 分析了蛋白质体降解,表面表达,蛋白质折叠和贩运途径,包括展开蛋白质反应的IRE1途径.
主要成果:
- 发现相关的NMDAR变体 (M705V,A727T) 是针对蛋白质体降解的,导致功能表面表达减少.
- 根据剂量,BIX治疗在HEK293T细胞中增强了这些变异的功能表面表达.
- 在人类iPSC衍生的神经元中,BIX的使用增加了M705V变体的表面蛋白水平.
- 通过IRE1通路的适度激活,BIX促进了M705V变体的折叠,抑制了降解,并增强了M705V变体的前级贩运.
结论:
- 调节ER蛋白质稳定网络可以恢复致病性NMDAR变体的折叠,贩运和功能.
- 向ER蛋白质稳定是一种有前途的治疗策略,用于因NMDAR功能障碍引起的神经系统疾病.
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