Developmental Neuroscience Project, Department of Brain and Neurosciences, Tokyo Metropolitan Institute of Medical Science, Setagaya, Japan.
Front Neural Circuits. 2021 Feb 10;15:595596. doi: 10.3389/fncir.2021.595596. eCollection 2021.
Heparan sulfate proteoglycans (HSPGs) are components of the cell surface and extracellular matrix, which bear long polysaccharides called heparan sulfate (HS) attached to the core proteins. HSPGs interact with a variety of ligand proteins through the HS chains, and mutations in HSPG-related genes influence many biological processes and cause various diseases. In particular, recent findings from vertebrate and invertebrate studies have raised the importance of glycosylphosphatidylinositol-anchored HSPGs, glypicans, as central players in the development and functions of synapses. Glypicans are important components of the synapse-organizing protein complexes and serve as ligands for leucine-rich repeat transmembrane neuronal proteins (LRRTMs), leukocyte common antigen-related (LAR) family receptor protein tyrosine phosphatases (RPTPs), and G-protein-coupled receptor 158 (GPR158), regulating synapse formation. Many of these interactions are mediated by the HS chains of glypicans. Neurexins (Nrxs) are also synthesized as HSPGs and bind to some ligands in common with glypicans through HS chains. Therefore, glypicans and Nrxs may act competitively at the synapses. Furthermore, glypicans regulate the postsynaptic expression levels of ionotropic glutamate receptors, controlling the electrophysiological properties and non-canonical BMP signaling of synapses. Dysfunctions of glypicans lead to failures in neuronal network formation, malfunction of synapses, and abnormal behaviors that are characteristic of neurodevelopmental disorders. Recent human genetics revealed that glypicans and HS are associated with autism spectrum disorder, neuroticism, and schizophrenia. In this review, we introduce the studies showing the roles of glypicans and HS in synapse formation, neural plasticity, and neurological disorders, especially focusing on the mouse and as potential models for human diseases.
硫酸乙酰肝素蛋白聚糖 (HSPGs) 是细胞表面和细胞外基质的组成部分，其核心蛋白上附着有长链多糖硫酸乙酰肝素 (HS)。HSPGs 通过 HS 链与各种配体蛋白相互作用，HSPG 相关基因的突变会影响多种生物学过程并导致各种疾病。特别是，脊椎动物和无脊椎动物研究的最新发现提高了糖基磷脂酰肌醇锚定 HSPG、聚糖作为突触发育和功能的核心参与者的重要性。聚糖是突触组织蛋白复合物的重要组成部分，作为富含亮氨酸重复跨膜神经元蛋白 (LRRTMs)、白细胞共同抗原相关 (LAR) 家族受体蛋白酪氨酸磷酸酶 (RPTPs) 和 G 蛋白偶联受体 158 (GPR158) 的配体，调节突触形成。这些相互作用中的许多都是通过聚糖的 HS 链介导的。神经连接蛋白 (Nrxs) 也作为 HSPGs 合成，并通过 HS 链与一些配体与聚糖共同结合。因此，聚糖和 Nrxs 可能在突触处竞争。此外，聚糖调节离子型谷氨酸受体的突触后表达水平，控制突触的电生理特性和非经典 BMP 信号转导。聚糖功能失调会导致神经元网络形成失败、突触功能障碍和神经发育障碍的异常行为。最近的人类遗传学研究表明，聚糖和 HS 与自闭症谱系障碍、神经质和精神分裂症有关。在这篇综述中，我们介绍了表明聚糖和 HS 在突触形成、神经可塑性和神经紊乱中的作用的研究，特别是侧重于小鼠和 作为人类疾病的潜在模型。
