Chronic and Acute Models of Retinal Neurodegeneration TrkA Activity Are Neuroprotective whereas p75NTR Activity Is Neurotoxic through a Paracrine Mechanism
Chronic and Acute Models of Retinal Neurodegeneration TrkA Activity Are Neuroprotective whereas p75NTR Activity Is Neurotoxic through a Paracrine Mechanism
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DOI：
10.1074/jbc.m110.147801
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发表时间：
2010-12-01
影响因子：
4.8
通讯作者：
Saragovi, H. Uri
中科院分区：
文献类型：
--
作者：
Bai, Yujing;Dergham, Pauline;Saragovi, H. Uri
在正常成人视网膜中，神经生长因子受体TrkA在视网膜神经节细胞（RGC）中表达，而神经胶质细胞表达p75（NTR）。在视网膜损伤期间，内源性神经生长因子、TrkA和p75（NTR）会上调。矛盾的是，无论是内源性神经生长因子还是外源性给予野生型神经生长因子，即使高频给药，都无法保护退化的视网膜神经节细胞。在此我们阐明了神经生长因子及其每种受体在体内对视网膜神经节细胞退化的相对作用。在因青光眼或视神经横断导致的视网膜退化过程中，使用仅激活TrkA的突变型神经生长因子进行治疗，或者使用一种生物反应调节剂来阻止内源性神经生长因子和前体神经生长因子与p75（NTR）结合，可提供显著的神经保护作用。用一种对神经生长因子突变体有选择性的p75（NTR）激动剂处理正常眼睛会导致视网膜神经节细胞进行性死亡，而在受伤的眼睛中则会加速视网膜神经节细胞死亡。在青光眼导致的视网膜退化过程中，p75（NTR）的作用机制是旁分泌的，通过增加神经毒性蛋白肿瘤坏死因子 -α和α₂ - 巨球蛋白的产生来实现。p75（NTR）拮抗剂在疾病过程中抑制肿瘤坏死因子 -α和α₂ - 巨球蛋白的上调，并提供神经保护作用。这些数据揭示了正常和患病视网膜中神经保护和神经毒性机制的平衡，并验证了每种神经营养因子受体可作为神经保护的药理学靶点。
In normal adult retinas, NGF receptor TrkA is expressed in retinal ganglion cells (RGC), whereas glia express p75(NTR). During retinal injury, endogenous NGF, TrkA, and p75(NTR) are up-regulated. Paradoxically, neither endogenous NGF nor exogenous administration of wild type NGF can protect degenerating RGCs, even when administered at high frequency. Here we elucidate the relative contribution of NGF and each of its receptors to RGC degeneration in vivo. During retinal degeneration due to glaucoma or optic nerve transection, treatment with a mutant NGF that only activates TrkA, or with a biological response modifier that prevents endogenous NGF and proNGF from binding to p75(NTR) affords significant neuroprotection. Treatment of normal eyes with an NGF mutant-selective p75(NTR) agonist causes progressive RGC death, and in injured eyes it accelerates RGC death. The mechanism of p75(NTR) action during retinal degeneration due to glaucoma is paracrine, by increasing production of neurotoxic proteins TNF-alpha and alpha(2)-macroglobulin. Antagonists of p75(NTR) inhibit TNF-alpha and alpha(2)-macroglobulin up-regulation during disease, and afford neuroprotection. These data reveal a balance of neuroprotective and neurotoxic mechanisms in normal and diseased retinas, and validate each neurotrophin receptor as a pharmacological target for neuroprotection.