中国神经再生研究(英文版) ›› 2013, Vol. 8 ›› Issue (4): 376-382.doi: 10.3969/j.issn.1673-5374.2013.04.010
收稿日期:
2012-07-30
修回日期:
2012-10-12
出版日期:
2013-02-05
发布日期:
2013-02-05
Jintang Wang1, Ling Yin2, Zheng Chen1
Received:
2012-07-30
Revised:
2012-10-12
Online:
2013-02-05
Published:
2013-02-05
Contact:
Zheng Chen, Master, Chief physician, Institute for Geriatric Clinic and Rehabilitation, Beijing Geriatric Hospital, Beijing 100095, China, paul_c99@ sina.com
About author:
Jintang Wang☆, M.D., Associate investigator.
Jintang Wang and Ling Yin contributed equally to this work.
Supported by:
This work was supported by a grant from the National Science and Technology Infrastructure Platform, Ministry of Science and Technology, No. 2005DKA32400
摘要:
帕金森病的主要发病机制是黑质纹状体系统的突触传递通路的改变,然而,近年来研究表明突触外传递也可通过细胞外基质的各向异性扩散方式参与该系统的多巴胺递质传递。文章综述了细胞外基质的主要成分纤维粘连蛋白在脑突触外传递中的神经保护作用。发现:①纤维粘连蛋白能调节神经活性物质的扩散和受体激活,具有抗神经炎症和神经保护作用。②纤维粘连蛋白可同时与整合素和生长因子受体结合,激活细胞内磷脂酰肌醇-3-激酶/丝苏氨酸蛋白激酶等信号通路,调节和放大生长因子样的神经保护作用。③纤维粘连蛋白在细胞周围汇集成纤维网络,促进细胞迁移、分子或离子扩散以及药物传送和治疗等。此外文章还分析了纤维粘连蛋白在帕金森病发病中的神经保护机制,包括与整合素和生长因子受体的相互作用,及纤维粘连蛋白在帕金森病治疗和诊断中的意义。
. 纤维粘连蛋白在脑突触外传递中的神经保护作用[J]. 中国神经再生研究(英文版), 2013, 8(4): 376-382.
Jintang Wang, Ling Yin, Zheng Chen. Neuroprotective role of fibronectin in neuron-glial extrasynaptic transmission[J]. Neural Regeneration Research, 2013, 8(4): 376-382.
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Along with other components of the extracellular matrix, such as glycosaminoglycans and proteoglycans, fibronectin accumulates in the extracellular matrix to form poriferous perineuronal nets to regulate matrix organization[46-47]. For example, fibronectin may specifically bind to growth factor receptors or be involved in clearance of degraded products and direct cell behaviors, such as receptor activation that transduces signals into cells, in addition to its supportive and adhesive roles. These effects of fibronectin could bring about the altered structural and functional properties of extracellular matrix (e.g., neurotransmitter storage, metabolite clearance, and diffusion parameters), and underlie the molecular mechanism of neurodegenerative disorders such as Parkinson’s disease[48]. The expression level of fibronectin determines the nature and condition of extracellular matrix, and is readily affected by multiple physiological and pathological factors (e.g., ageing and neuroinflammatory response), as well as genetic and epigenetic factors (e.g., transcription factors and post-translational modifications)[8-9]. Meanwhile, fibronectin, like other extracellular matrix macromolecules, contributes to diffusion barriers in the extracellular space and influences neuroglial activation, diffusion of various factors or neurotransmitters, information transmission and neurotrophic microenvironment[4, 47], in spite of neuronal and glial processes also disturbing the local extracellular matrix architecture of the central nervous system. The neuroprotective mechanism of fibronectin is mediated by both integrins and growth factor receptors[16-17, 20]. Briefly, binding of fibronectin to integrins (β1, β2, and αv) triggers intracellular structural alterations and signaling cascades, including integrin-mediated signaling which can crosstalk with growth factor-mediated signaling at various levels[49] and mimic the functions of growth factors via receptor transactivation and intracellular signaling events. Therefore, fibronectin could be applied to study neuroprotection in neurodegenerative diseases such as Parkinson’s disease. In the Parkinson’s disease brain, the transmission of dopamine in the nigrostriatal pathway is greatly abated or blocked for two reasons: 1) deficit of striatal dopamine in the Parkinson’s disease brain because of decreased dopamine synthesis in degenerating nigral neurons, and 2) altered matrix content and increased diffusion barriers to extrasynaptic transmission along the nigrostriatal pathway. The latter is the main pathological change in the Parkinson’s disease brain because the nigrostriatal dopamine pathway mainly operates via volume transmission; that is, nigral dopamine reaches target cells mostly by diffusion along the dopamine concentration gradient of the extracellular space[5, 50]. Although the downregulated expression of fibronectin in the elderly brain can compensative and reduce the diffusion barrier and partly ameliorate deficits in dopamine diffusion, the increased volume fraction is still not reversed[6, 48]. Therefore, fibronectin could be administered as a neuroprotective drug to augment the fibronectin levels in plasma and brain, which would not only enhance survival of dopaminergic neurons but would also maintain a better extracellular matrix status for unrestricted diffusion and traffic of dopamine along the nigrostriatal pathway. In particular, under circumstances in which wiring transmission is blocked, the use of extrinsic fibronectin has an important compensatory effect on the striatal dopamine deficit and protects against the development of Parkinson’s disease[43-44, 48]. Moreover, it is reasonable to predict that the molecular status of plasma fibronectin could be used as an additional diagnostic biomarker for risk assessment of Parkinson’s disease[51], and that the increase of fibronectin in the cerebrospinal fluid could be an important parameter used to diagnose certain neurodegenerative diseases such as amyotrophic lateral sclerosis and multiple sclerosis[51]. The proneuronal and metabolic effects of fibronectin will be helpful in formulating new therapeutic and diagnostic strategies.
1 This study reviewed the neuroprotective effect of fibronectin, a major extracellular matrix component, in extrasynaptic transmission and its possible therapeutic and diagnostic significance for Parkinson’s disease. 2 Evidence showed that fibronectin can bind to integrins and growth factor receptors (such as insulin-like growth factor 1 receptor) to transactivate intracellular signaling events, such as the phosphatidylinositol 3-kinase/protein kinase B pathway, and regulate or amplify growth factor-like neuroprotective actions. 文章全面综述了细胞外基质的主要成分纤维粘连蛋白在脑突触外传递中的神经保护作用及其在帕金森病诊断和治疗中的潜在应用价值。发现纤维粘连蛋白主要通过与整合素和生长因子(如胰岛素生长因子1)受体结合,激活细胞内磷脂酰肌醇-3-激酶/丝苏氨酸蛋白激酶等信号通路发挥神经保护作用。
③生长因子如IGF-1除了自身的神经保护作用外,其受体还可得到细胞外基质中许多活性分子的激活,成为神经保护性信号转导通路的主流。
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