The proNGF-p75NTR-Sortilin Signalling Complex as New Target for the Therapeutic Treatment of Parkinson's Disease
The proNGF-p75NTR-Sortilin Signalling Complex as New Target for the Therapeutic Treatment of Parkinson's Disease
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DOI：
10.2174/187152708787122923
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发表时间：
2008-12-01
影响因子：
3
通讯作者：
Bolam, J. P.
中科院分区：
文献类型：
--
作者：
Chen, L. W.;Yung, K. K. L.;Bolam, J. P.
越来越多的证据表明，p75神经营养素受体(P75NTR)可能在中枢神经系统发育过程中控制神经元存活或细胞凋亡，以及在病理或神经损伤中发挥重要作用。最近的研究进一步揭示，p75NTR是一个分子信号开关，通过三个过程决定细胞的死亡或存活。首先，前神经生长因子(ProNGF)通过与p75NTR的高亲和力结合而触发细胞凋亡，而NGF通过低亲和力结合诱导神经元存活。第二，p75NTR通过与辅受体sortilin结合来介导细胞死亡，而p75NTR通过与proNGF结合来促进神经元存活。第三，释放细胞内域切断器或裂解的“短p75NTR”可以独立地启动神经元的凋亡。我们在黑质致密部腹侧层多巴胺神经元中发现了细胞自毁的proNGF-p75NTR-sortilin信号转导装置，提示p75NTR信号可能参与了黑质神经元选择性死亡机制或帕金森病(PD)的疾病进展。此外，p75NTR的实验操作有利于胆碱能神经元或运动神经元的细胞存活，并改善了神经退行性疾病阿尔茨海默病和肌萎缩侧索硬化症的疾病进展。因此，proNGF-p75NTR-sortilin信号复合体可能为黑质神经元的神经保护和帕金森病的治疗提供新的靶点。
Growing evidence has shown that the p75 neurotrophin receptor (p75NTR) may play important roles in controlling neuronal survival or cell apoptosis within the central nervous system in development, and in pathological or neural injury. Recent studies have further revealed that p75NTR acts as a "molecular signal switch" that determines cell death or survival by three processes. First, pro-nerve growth factor (proNGF) triggers cell apoptosis by its high affinity binding to p75NTR, while NGF induces neuronal survival with low-affinity binding. Second, p75NTR mediates cell death by combining with co-receptor sortilin, whereas it promotes neuronal survival through combination with proNGF. Third, release of the intracellular domain chopper or cleavaged "short p75NTR" can independently initiate neuronal apoptosis. We have identified the cell self-destructive proNGF-p75NTR-sortilin signalling apparatus assembled in ventral tier dopamine neurons of the substantia nigra pars compacta, suggesting that p75NTR signalling might be involved in selective cell death mechanisms of substantia nigra neurons or disease progression of Parkinson's disease (PD). In addition, experimental manipulation of p75NTR benefited cell survival of cholinergic or motor neurons and improved disease progression of the neurodegenerative diseases Alzheimer's disease and Amyotrophic lateral sclerosis. The proNGF-p75NTR-sortilin signalling complex may thus provide new target for neuroprotection of substantia nigra neurons and the therapeutic treatment of PD.