蛋白质与蛋白质相互作用干扰可以拯救失调的NMDA受体信号传递
Robert E Featherstone1, Hongbin Li2, Ameet S Sengar2
1Department of Psychiatry and the Behavioral Sciences, University of Southern California, Los Angeles, United States of America.
JCI insight
|December 4, 2025
概括
针对N-甲基-D-酸盐受体 (NMDAR) 综合体中的蛋白相互作用,为神经精神疾病提供了一种新的治疗策略. 一种酸成功地逆转了NMDAR低功率和精神分裂症小鼠模型中的认知缺陷.
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
- 精神病学是一个精神病学.
背景情况:
- 神经精神疾病具有复杂的遗传基础,需要超越个体基因的治疗策略.
- 在N-甲基-D-酸盐受体 (NMDAR) 复合体内的蛋白-蛋白相互作用 (PPI) 涉及到趋同的风险路径.
- 在精神分裂症中,NMDAR的低功能与由于其PPI的变化而改变的Src激酶活性有关,特别是PSD-95,它抑制Src.
研究的目的:
- 开发和测试一种基于的策略,以破坏抑制性Src-PSD-95相互作用.
- 研究该在逆转NMDAR低功能的治疗潜力和认知缺陷.
主要方法:
- 开发一种细胞透 (TAT-SAPIP),旨在抑制Src-PSD-95结合.
- 向表现NMDAR低功能的表型的小鼠模型 (Src+/-和Sdy-/-) 给予TAT-SAPIP.
- 评估突触NMDAR电流,脑组织中的Src活性和认知功能 (跟踪恐惧调节).
主要成果:
- 在NMDAR功能低下的小鼠模型中,TAT-SAPIP增强了突触NMDAR电流.
- 在Src+/-小鼠中,慢性服用TAT-SAPIP可挽救认知缺陷.
- 该增加了患者和健康受试者的synaptoneurosomes中的Src活性.
结论:
- 阻止Src-PSD-95相互作用是一种可行的治疗方法.
- 干扰像TAT-SAPIP这样的对治疗精神分裂症和相关疾病的NMDAR低功能的治疗有希望.
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