摘要
多发性硬化症(multiple sclerosis,MS)是一种自身免疫性疾病,主要表现为脱髓鞘和神经炎症。作为年轻人中最常见的非创伤性致残原因,MS在全球范围内导致数百万人瘫痪。MS的确切发病机制尚未完全明确,目前尚无治愈方法。硫酸软骨素蛋白聚糖(chondroitin sulfate proteoglycans,CSPGs)是一类抑制性细胞外基质分子,其受体蛋白酪氨酸磷酸酶σ(protein tyrosine phosphataseσ,PTPσ)在CSPGs介导的轴突再生抑制中起关键作用。研究表明,CSPGs/PTPσ在MS的发生和发展中也具有重要作用,并在MS病变区域的细胞外基质中上调。动物实验发现,抑制CSPGs/PTPσ信号途径可以促进少突胶质前体细胞(oligodendrocyte precursor cells,OPC)的迁移、分化、髓鞘再生,并恢复运动功能,显示出治疗MS的潜力。本文综述了CSPGs/PTPσ在中枢神经系统髓鞘再生研究中的最新进展,旨在为MS的治疗提供新的策略和靶点。
Multiple sclerosis(MS)is a chronic autoimmune disease of the central nervous system(CNS)characterized by progressive demyelination and neuroinflammation,leading to axonal damage and neuronal degeneration.It is the most prevalent non-traumatic cause of neurological disability in young adults,affecting millions of people worldwide.MS manifests with a wide range of symptoms,including motor dysfunction,sensory deficits,and cognitive impairment,which can severely impact the quality of life.Despite extensive research,the exact pathogenesis of MS remains unclear,and currently available treatments primarily focus on reducing inflammation and relapse rates rather than reversing neurological damage.Thus,one of the major therapeutic challenges is to develop strategies that can not only suppress the aberrant immune response but also enhance endogenous myelin regeneration and neurorepair,ultimately halting or even reversing disease progression.Recent studies have highlighted the critical role of chondroitin sulfate proteoglycans(CSPGs),a family of inhibitory extracellular matrix(ECM)molecules,in regulating CNS repair processes.CSPGs accumulate at the sites of demyelinated lesions and form a dense,inhibitory matrix that impedes the migration and differentiation of oligodendrocyte precursor cells(OPCs),thereby preventing effective myelin regeneration.CSPGs exert their inhibitory effects through several cell surface receptors,including leukocyte common antigen-related receptor(LAR),Nogo receptors(NgR1 and NgR3),and protein tyrosine phosphataseσ(PTPσ).Among these,PTPσis a predominant receptor that mediates the biological activities of CSPGs via its phosphatase domains,which regulate downstream signaling pathways involved in cell proliferation,differentiation,and cytoskeletal organization.The CSPGs/PTPσaxis has been identified as a major molecular pathway contributing to the inhibition of remyelination in MS.The upregulation of CSPGs and PTPσin MS lesions has been associated with a failure of OPCs to remyelinate damaged axons effectively.Preclinical studies have shown that pharmacological inhibition or genetic ablation of PTPσcan alleviate the inhibitory effects of CSPGs on OPC migration and differentiation.For instance,systemic administration of the PTPσinhibiting peptide intracellular sigma peptide(ISP)has been shown to enhance OPC differentiation,promote remyelination,and restore motor function in animal models of MS,highlighting the potential of targeting CSPGs/PTPσas a therapeutic approach for MS.Furthermore,CSPGs and their receptors have been implicated in modulating other biological processes such as immune cell infiltration,synaptic plasticity,and axonal regeneration,which are relevant to the pathogenesis of MS and other neurodegenerative diseases.CSPGs are known to activate downstream signaling pathways,such as the Rho/ROCK,Akt,and ERK pathways,which regulate cytoskeletal dynamics and gene expression in OPCs,ultimately affecting their ability to mature into myelinating oligodendrocytes.Additionally,CSPGs can interact with the N-cadherin/β-catenin pathway,influencing cell adhesion and signaling in OPCs,thereby modulating myelin repair capacity.Given the multifaceted roles of CSPGs/PTPσin CNS pathology,targeting this pathway represents a promising therapeutic strategy.This article aims to provide a comprehensive overview of the biological properties of CSPGs and PTPσ,focusing on their roles in the inhibition of myelin regeneration.Specifically,it discusses how CSPGs/PTPσsignaling modulates various aspects of OPC biology,including autophagy regulation and immune modulation.Moreover,the review explores potential therapeutic strategies aimed at disrupting CSPGs/PTPσinteractions,such as the use of small-molecule inhibitors,neutralizing antibodies,or gene therapies.In summary,a deeper understanding of CSPGs/PTPσ-mediated signaling in OPCs and other cell types within MS lesions may reveal novel therapeutic targets for promoting remyelination and functional recovery.This review provides a detailed analysis of current findings and highlights the need for further research to translate these findings into effective treatments for MS patients.
作者
王敬桐
罗富成
陈文利
WANG Jing-Tong;LUO Fu-Cheng;CHEN Wen-Li(State Key Laboratory of Primate Biomedical Research,Institute of Primate Translational Medicine,Kunming University of Science and Technology,Kunming 650500,China;Department of Neurology,Yunnan First People’s Hospital,Kunming 650032,China)
出处
《生物化学与生物物理进展》
北大核心
2025年第3期592-602,共11页
Progress In Biochemistry and Biophysics
基金
云南省科技厅-昆明医科大学应用基础研究联合专项(202101AY070001-237)
云南省基础研究计划(202301AT070412)资助。
