摘要
正常眼压性青光眼(NTG)是原发性开角型青光眼(POAG)的独立亚型,特征为眼压正常(<21 mmHg)但出现进行性视神经病变、视网膜神经节细胞(RGC)凋亡及视野缺损。其发病机制主要为非眼压依赖,核心涉及以基因与线粒体为中心的过程,包括RGC退变、神经炎症、线粒体功能障碍和遗传易感性。基于此,本文系统梳理NTG的非眼压依赖、基因驱动机制,重点解析OPTN、TBK1、FOXC1与OPA1如何通过线粒体功能紊乱、胶质细胞激活、炎症信号、细胞凋亡与轴突退化等途径导致RGC损伤。其中,OPTN和TBK1基因通过自噬-线粒体稳态失调、轴突运输缺陷及神经炎症通路共同促进NTG的发生。FOXC1通过转录调控参与RGC进化过程;OPA1突变触发线粒体依赖的RGC凋亡。此外,本文还综述METTL23的表观遗传调控、线粒体DNA突变、Alcadeinα在轴突运输中的作用、POAG相关基因与NTG的关联,以及全基因组关联研究(GWAS)揭示的易感位点。转化研究方面,近期治疗的研究进展包括针对OPTN E50K的干预、抑制CRMP2磷酸化、基因增补、基因沉默与基因编辑等策略。NTG病因复杂且主要为非眼压依赖,由遗传与环境因素相互作用所致。本文旨在推进基于机制的技术创新、优化NTG神经保护策略并强化临床转化,以实现精准治疗并改善患者视功能结局。
Normal tension glaucoma(NTG)is recognized as a distinct subtype of primary open-angle glaucoma,characterized by normal intraocular pressure(IOP<21 mmHg)in conjunction with progressive optic neuropathy,retinal ganglion cell(RGC)apoptosis,and visual field defects.The pathogenesis of NTG is predominantly independent of IOP,with fundamental processes involving genetic and mitochondrial factors,including RGC degeneration,neuroinflammation,mitochondrial dysfunction,and genetic predisposition.This article systematically reviews the IOP-independent and gene-driven mechanisms underlying NTG,with a particular focus on the roles of OPTN,TBK1,FOXC1,and OPA1 in inducing RGC damage through pathways such as mitochondrial dysfunction,glial cell activation,inflammatory signaling,apoptosis,and axonal degeneration.Among these genes,OPTN and TBK1 collectively contribute to the development of NTG by disrupting autophagy-mitochondrial homeostasis,causing defects in axonal transport,and activating neuroinflammatory pathways.FOXC1 is implicated in the progression of RGC degeneration through transcriptional regulation,while mutations in OPA1 lead to mitochondria-dependent RGC apoptosis.Additionally,this article provides a comprehensive review of the epigenetic regulation of METTL 23,mitochondrial DNA mutations,the role of Alcadeinαin axonal transport,the correlation between genes associated with primary open-angle glaucoma(POAG)and normal tension glaucoma(NTG),as well as susceptibility loci identified through genome-wide association studies(GWAS).In the realm of translational research,recent advancements in therapeutic studies encompass strategies such as targeting OPTN E 50 K,inhibiting CRMP 2 phosphorylation,and employing gene augmentation,gene silencing,and gene editing techniques.The etiology of NTG is complex,predominantly independent of intraocular pressure(IOP),and arises from the interplay between genetic and environmental factors.This article seeks to promote mechanism-based technological innovation,optimize neuroprotective strategies for NTG,and enhance clinical translation,ultimately aiming to achieve precise treatment and improve visual function outcomes for patients.
作者
胡昊
梁亮
HU Hao;LIANG Liang(Department of Ophthalmology,The Second People’s Hospital of China Three Gorges University、The Second People’s Hospital of Yichang,Yichang 443000,China)
出处
《中山大学学报(医学科学版)》
北大核心
2025年第6期945-954,共10页
Journal of Sun Yat-Sen University:Medical Sciences
基金
国家自然科学基金(81770920)
眼科学国家重点实验室开放课题(303060202400383)。
