cGAS-STING通路在神经退行性疾病中的作用

Roles of cGAS-STING pathway in neurodegenerative diseases

外来或自身错位的核酸通过激活胞质DNA传感器环GMP-AMP合成酶(cyclic GMP-AMP synthase,cGAS)并结合其下游信号效应干扰素基因刺激因子(stimulator of interferon genes,STING)触发先天免疫反应。许多神经退行性疾病都显示出激活的炎症表型,靶向cGAS-STING通路的小分子调节剂成为治疗大多数涉及型干扰素水平升高和促炎细胞因子增加的神经退行性疾病的关键。本文总结了cGAS-STING通路在多种神经退行性脑部疾病,如阿尔茨海默病(Alzheimer’s disease,AD)、亨廷顿病(Huntington’s disease,HD)、帕金森病(Parkinson’s disease,PD)以及肌萎缩侧索硬化症(Amyotrophic lateral sclerosis,ALS)等中发挥的重要功能机制的最新研究进展,并讨论cGAS-STING小分子调节剂如cGAS抑制剂和STING抑制剂在这些疾病中可能的治疗作用,为大多数神经退行性疾病的药物治疗提供新策略。

Foreign or self-mislocated nucleic acids trigger innate immune responses by activating the cytosolic DNA sensor cyclic GMP-AMP synthase(cGAS)and binding to its downstream signaling effector stimulator of interferon genes(STING).Since neurodegenerative diseases show an activated inflammatory phenotype,small molecule modulators targeting the c GAS-STING pathway hold the key to the treatment of most neurodegenerative diseases involving elevated levels of type I interferons and increased proinflammatory cytokines.In this review,we will summarize the fundamental roles of cGAS-STING pathway in various neurodegenerative diseases,such as Alzheimer’s disease(AD),Huntington’s disease(HD),Parkinson’s disease(PD)and amyotrophic lateral sclerosis(ALS),and discuss the possible therapeutic effects of small molecule modulators targeting cGAS-STING pathway such as c GAS inhibitors and STING inhibitors in these diseases,providing new strategies for the medical treatment of most neurodegenerative diseases.