蛋白聚糖硫酸化在成熟中枢神经系统功能中的作用

Proteoglycan Sulphation in the Function of the Mature Central Nervous System.

作者信息

Fawcett James W, Kwok Jessica C F

机构信息

Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom.

Centre for Reconstructive Neuroscience, Institute for Experimental Medicine Czech Academy of Science (CAS), Prague, Czechia.

出版信息

Front Integr Neurosci. 2022 May 30;16:895493. doi: 10.3389/fnint.2022.895493. eCollection 2022.

Abstract

Chondroitin sulphate and heparan sulphate proteoglycans (CSPGS and HSPGs) are found throughout the central nervous system (CNS). CSPGs are ubiquitous in the diffuse extracellular matrix (ECM) between cells and are a major component of perineuronal nets (PNNs), the condensed ECM present around some neurons. HSPGs are more associated with the surface of neurons and glia, with synapses and in the PNNs. Both CSPGs and HSPGs consist of a protein core to which are attached repeating disaccharide chains modified by sulphation at various positions. The sequence of sulphation gives the chains a unique structure and local charge density. These sulphation codes govern the binding properties and biological effects of the proteoglycans. CSPGs are sulphated along their length, the main forms being 6- and 4-sulphated. In general, the chondroitin 4-sulphates are inhibitory to cell attachment and migration, while chondroitin 6-sulphates are more permissive. HSPGs tend to be sulphated in isolated motifs with un-sulphated regions in between. The sulphation patterns of HS motifs and of CS glycan chains govern their binding to the PTPsigma receptor and binding of many effector molecules to the proteoglycans, such as growth factors, morphogens, and molecules involved in neurodegenerative disease. Sulphation patterns change as a result of injury, inflammation and ageing. For CSPGs, attention has focussed on PNNs and their role in the control of plasticity and memory, and on the soluble CSPGs upregulated in glial scar tissue that can inhibit axon regeneration. HSPGs have key roles in development, regulating cell migration and axon growth. In the adult CNS, they have been associated with tau aggregation and amyloid-beta processing, synaptogenesis, growth factor signalling and as a component of the stem cell niche. These functions of CSPGs and HSPGs are strongly influenced by the pattern of sulphation of the glycan chains, the sulphation code. This review focuses on these sulphation patterns and their effects on the function of the mature CNS.

摘要

硫酸软骨素和硫酸乙酰肝素蛋白聚糖(CSPGs和HSPGs)遍布于中枢神经系统(CNS)。CSPGs在细胞间弥漫性的细胞外基质(ECM)中普遍存在,是神经元周围网(PNNs)的主要成分,神经元周围网是存在于某些神经元周围的致密ECM。HSPGs更多地与神经元和神经胶质细胞的表面、突触以及PNNs相关。CSPGs和HSPGs都由一个蛋白核心组成,在该核心上连接着重复的二糖链,这些二糖链在不同位置被硫酸化修饰。硫酸化序列赋予这些链独特的结构和局部电荷密度。这些硫酸化编码决定了蛋白聚糖的结合特性和生物学效应。CSPGs在其长度上被硫酸化,主要形式为6-硫酸化和4-硫酸化。一般来说,4-硫酸软骨素抑制细胞附着和迁移,而6-硫酸软骨素则更具通透性。HSPGs倾向于在孤立的基序中被硫酸化,其间有未硫酸化的区域。HS基序和CS聚糖链的硫酸化模式决定了它们与PTPsigma受体的结合以及许多效应分子与蛋白聚糖的结合,如生长因子、形态发生素以及参与神经退行性疾病的分子。硫酸化模式会因损伤、炎症和衰老而发生变化。对于CSPGs,研究重点集中在PNNs及其在可塑性和记忆控制中的作用,以及在胶质瘢痕组织中上调且能抑制轴突再生的可溶性CSPGs。HSPGs在发育过程中发挥关键作用,调节细胞迁移和轴突生长。在成体CNS中,它们与tau蛋白聚集和淀粉样β蛋白加工、突触形成、生长因子信号传导相关,并且是干细胞微环境的组成部分。CSPGs和HSPGs的这些功能受到聚糖链硫酸化模式即硫酸化编码的强烈影响。本综述聚焦于这些硫酸化模式及其对成熟CNS功能的影响。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d16/9195417/083189582674/fnint-16-895493-g001.jpg

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