摘要
背景:理清诸多信号通路与轴突病理改变的交互关系,探明轴突退变在帕金森病发生、发展过程中的作用及机制,有利于围绕轴突退行性变开展帕金森病发病及病变机制研究。目的:深入分析轴突损伤和修复的主要信号通路在帕金森病发生与发展过程中的作用及相互关系,揭示潜在的临床早期预警机制,并探索靶向基因靶位、药物治疗和康复干预等新型防治策略。方法:检索PubMed和中国知网数据库,英文检索词为“Parkinson,PD,axonal degeneration,aging,α-syn,pathological mechanism,autopsy,mitochondria,ER stress,inflammatory response,Nrf2/Keap1,BDNF,NGF,NT3/TrkC,GDNF,RhoA,Rac/Cdc42,Wnt/β-catenin,SHH,Notch,Slit-Robo,Ephrin,Netrin,Semaphorin,integrin,ubiquitin-proteasome,autophagy-lysosome,apoptosis,exercise”,中文检索词为“帕金森,轴突退变,运动,氧化应激,脑源性神经营养因子”,按照纳入和排除标准对文献进行筛选,最终纳入101篇文献进行综述分析。结果与结论:研究表明,帕金森病的病变最初发生在大脑边缘系统区域或嗅球,并且早期的轴突退化通常先于胞体退化。异常蛋白质的折叠与聚集、线粒体功能失调、内质网应激及炎症反应等多条信号通路可能直接导致轴突损伤;同时,细胞应激反应、神经营养因子的作用、细胞骨架的调控、发育和再生、轴突的生长与引导以及异常蛋白质的清除等信号通路则有助于修复受损的轴突。因此,帕金森病的防治策略应着重于促进修复通路的激活与表达,例如,奎纳克林和氯硝柳胺的使用或通过运动激活脑源性神经营养因子等轴突修复通路的表达,可以有效促进轴突修复;与此同时,抑制损伤通路的异常激活也是防治的关键策略,此类策略包括通过敲除α-突触核蛋白、Parkin等基因或使用恩格列净等药物减少氧化应激和炎症反应,从而可能有效延缓帕金森病的进展。
BACKGROUND:Clarifying the interactions between multiple signaling pathways and axonal pathological alterations,and elucidating the role and mechanisms of axonal degeneration in the onset and progression of Parkinson’s disease will pave the way for research on the pathogenesis and pathological mechanisms of Parkinson’s disease centered around axonal degenerative changes.OBJECTIVE:Through in-depth analysis of the roles and interactions of the signaling pathways mentioned in this review during the occurrence and development of Parkinson’s disease,to uncover potential clinical early warning mechanisms and explore novel strategies for prevention and treatment,including targeted gene sites,drug therapy,and rehabilitation interventions.METHODS:A search of the PubMed database was conducted using the following keywords:“Parkinson,PD,axonal regeneration,aging,α-syn,pathological mechanism,autopsy,mitochondria,ER stress,inflammatory response,Nrf2/Keap1,BDNF,NGF,NT3/TrkC,GDNF,RhoA,Rac/Cdc42,Wnt/β-catenin,SHH,Notch,Slit-Robo,Ephrin,Netrin,Semaphorin,integrin,ubiquitin-proteasome,autophagy-lysosome,apoptosis,exercise.”Another search of CNKI database was conducted using the search terms of“Parkinson’s,axonal degeneration,exercise,oxidative stress,brain-derived neurotrophic factor.”Literature was screened based on inclusion and exclusion criteria,and 101 articles were finally included for review and analysis.RESULTS AND CONCLUSION:Studies have shown that Parkinson’s disease lesions initially occur in the limbic system region of the brain or the olfactory bulb,and that early axonal degeneration usually precedes cytosolic degeneration.Abnormal protein folding and aggregation,mitochondrial dysfunction,endoplasmic reticulum stress,and inflammatory responses are among the signaling pathways that may directly lead to axonal damage.At the same time,signaling pathways involved in cellular stress responses,neurotrophic factors,cytoskeletal regulation,development and regeneration,axonal growth and guidance,and removal of abnormal proteins contribute to the repair of damaged axons.Therefore,the prevention and treatment strategies for Parkinson’s disease,should focus on promoting the activation and expression of repair pathways.For instance,the use of quinacrine and clorgiline or the activation of brain-derived neurotrophic factor expression through exercise may effectively facilitate axonal repair.Additionally,inhibiting the aberrant activation of damage-related pathways is a crucial aspect of treatment strategies.Such approaches include gene knockout ofα-synuclein,Parkin,or the use of drugs like empagliflozin to reduce oxidative stress and inflammation,potentially delaying the progression of Parkinson’s disease.
作者
王姣
宋文君
辛睿
刘伟
英振昊
Wang Jiao;Song Wenjun;Xin Rui;Liu Wei;Ying Zhenhao(Shandong University of Traditional Chinese Medicine,Jinan 250355,Shandong Province,China)
出处
《中国组织工程研究》
北大核心
2026年第28期7370-7377,共8页
Chinese Journal of Tissue Engineering Research
基金
国家自然科学基金项目(82174367),项目负责人:刘伟
山东中医药大学科学研究基金项目(KYZK2024M08),项目负责人:英振昊。
关键词
帕金森病
轴突退变
信号通路
损伤
修复
Α-突触核蛋白
活性氧
脑源性神经营养因子
Parkinson’s disease
axonal degeneration
signaling pathway
injury
repair
α-synuclein
reactive oxygen species
brain-derived neurotrophic factor
