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Collagen in the central nervous system: contributions to neurodegeneration and promise as a therapeutic target
Molecular Neurodegeneration ( IF 14.9 ) Pub Date : 2024-01-25 , DOI: 10.1186/s13024-024-00704-0
Lauren K Wareham 1 , Robert O Baratta 2 , Brian J Del Buono 2 , Eric Schlumpf 2 , David J Calkins 1
Affiliation  

The extracellular matrix is a richly bioactive composition of substrates that provides biophysical stability, facilitates intercellular signaling, and both reflects and governs the physiological status of the local microenvironment. The matrix in the central nervous system (CNS) is far from simply an inert scaffold for mechanical support, instead conducting an active role in homeostasis and providing broad capacity for adaptation and remodeling in response to stress that otherwise would challenge equilibrium between neuronal, glial, and vascular elements. A major constituent is collagen, whose characteristic triple helical structure renders mechanical and biochemical stability to enable bidirectional crosstalk between matrix and resident cells. Multiple members of the collagen superfamily are critical to neuronal maturation and circuit formation, axon guidance, and synaptogenesis in the brain. In mature tissue, collagen interacts with other fibrous proteins and glycoproteins to sustain a three-dimensional medium through which complex networks of cells can communicate. While critical for matrix scaffolding, collagen in the CNS is also highly dynamic, with multiple binding sites for partnering matrix proteins, cell-surface receptors, and other ligands. These interactions are emerging as critical mediators of CNS disease and injury, particularly regarding changes in matrix stiffness, astrocyte recruitment and reactivity, and pro-inflammatory signaling in local microenvironments. Changes in the structure and/or deposition of collagen impact cellular signaling and tissue biomechanics in the brain, which in turn can alter cellular responses including antigenicity, angiogenesis, gliosis, and recruitment of immune-related cells. These factors, each involving matrix collagen, contribute to the limited capacity for regeneration of CNS tissue. Emerging therapeutics that attempt to rebuild the matrix using peptide fragments, including collagen-enriched scaffolds and mimetics, hold great potential to promote neural repair and regeneration. Recent evidence from our group and others indicates that repairing protease-degraded collagen helices with mimetic peptides helps restore CNS tissue and promote neuronal survival in a broad spectrum of degenerative conditions. Restoration likely involves bolstering matrix stiffness to reduce the potential for astrocyte reactivity and local inflammation as well as repairing inhibitory binding sites for immune-signaling ligands. Facilitating repair rather than endogenous replacement of collagen degraded by disease or injury may represent the next frontier in developing therapies based on protection, repair, and regeneration of neurons in the central nervous system.

中文翻译:


中枢神经系统中的胶原蛋白:对神经退行性变的贡献并有望成为治疗靶点



细胞外基质是一种具有丰富生物活性的底物组成物,可提供生物物理稳定性,促进细胞间信号传导,并反映和控制局部微环境的生理状态。中枢神经系统 (CNS) 中的基质远非简单的机械支撑惰性支架,而是在体内平衡中发挥积极作用,并为应对压力提供广泛的适应和重塑能力,否则会挑战神经元、神经胶质细胞和血管元素之间的平衡。胶原蛋白是一种主要成分,其特有的三螺旋结构具有机械和生化稳定性,可实现基质细胞和驻留细胞之间的双向串扰。胶原蛋白超家族的多个成员对大脑中的神经元成熟和回路形成、轴突导向和突触形成至关重要。在成熟组织中,胶原蛋白与其他纤维蛋白和糖蛋白相互作用,以维持三维介质,复杂的细胞网络可以通过该介质进行交流。虽然对基质支架至关重要,但 CNS 中的胶原蛋白也是高度动态的,具有多个结合位点,用于配对基质蛋白、细胞表面受体和其他配体。这些相互作用正在成为 CNS 疾病和损伤的关键介质,特别是关于基质刚度、星形胶质细胞募集和反应性以及局部微环境中促炎信号的变化。胶原蛋白结构和/或沉积的变化会影响大脑中的细胞信号传导和组织生物力学,进而改变细胞反应,包括抗原性、血管生成、神经胶质增生和免疫相关细胞的募集。 这些因素都涉及基质胶原,导致 CNS 组织的再生能力有限。试图使用肽片段重建基质的新兴疗法,包括富含胶原蛋白的支架和模拟物,在促进神经修复和再生方面具有巨大潜力。我们小组和其他人的最新证据表明,用模拟肽修复蛋白酶降解的胶原螺旋有助于恢复 CNS 组织并促进神经元在广泛的退行性疾病中的存活。恢复可能涉及增强基质刚度以减少星形胶质细胞反应性和局部炎症的可能性,以及修复免疫信号配体的抑制性结合位点。促进修复而不是内源性替代因疾病或损伤而降解的胶原蛋白可能代表了开发基于中枢神经系统神经元保护、修复和再生的疗法的下一个前沿。
更新日期:2024-01-25
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