Role of crystallins in ocular neuroprotection and axonal regeneration
Role of crystallins in ocular neuroprotection and axonal regeneration
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DOI：
10.1016/j.preteyeres.2014.06.004
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发表时间：
2014-09-01
影响因子：
17.8
通讯作者：
Heiligenhaus, Arndt
中科院分区：
文献类型：
--
作者：
Thanos, Solon;Boehm, Michael R. R.;Heiligenhaus, Arndt
由于视网膜神经元的特别暴露位置以及应用于各种眼部疾病的眼内手术和药物治疗的稳定增加率，神经保护是眼科学中的一个新兴挑战。在几十年内，神经保护已经从强烈争议的方法发展到被认可并作为潜在的临床应用引入。一组推定的神经保护物质包括α A-和α B-晶体蛋白，它们是热休克蛋白的类型，被认为是分子伴侣。β/γ-晶体蛋白形成它们自己的超家族，并且被表征为具有包含四个希腊关键基序的独特结构的蛋白质。除了在眼透镜中丰富外，晶状体蛋白还在发育和成熟的视网膜中表达。晶体蛋白在许多视网膜病变中显著上调，包括机械损伤、缺血性损伤、年龄相关性黄斑变性、葡萄膜视网膜炎和糖尿病视网膜病变。α家族的晶体蛋白被认为在视网膜神经元存活和炎症中起关键作用。β/γ超家族的晶体蛋白也是在视网膜组织重塑和修复中具有可能的新兴作用的小蛋白质。与晶状体蛋白相关的典型视网膜疾病之一是以其表达为特征的实验性青光眼性神经病。另一种典型的视网膜疾病是视神经机械损伤后发生的萎缩，这与视网膜轴突再生的需要有关。我们在体内和体外再生模型中表明，β B2-晶状体蛋白积极支持切割视网膜轴突的再生生长，从而为神经保护和再生治疗提供靶点。在这篇综述中，我们讨论的发现，β B2-晶体蛋白是明确上调在体外再生视网膜。β B2-晶体蛋白在轴突伸长期间产生和分泌，而β/γ-晶体蛋白通过直接摄取到细胞中或间接通过增强来自星形胶质细胞的睫状神经营养因子的产生以协同促进轴突再生长而在体内和体外促进轴突生长。我们还讨论了基于使用转染的神经祖细胞在损伤和修复部位诱导晶体蛋白连续产生的方法。这篇综述最终得出的结论是，神经元的损伤后命运不能仅仅被视为不可避免的，而是应该被视为塑造促进细胞存活和轴突修复的神经保护和再生条件的挑战。(C)2014爱思唯尔有限公司版权所有。
Neuroprotection is an emerging challenge in ophthalmology due to the particularly exposed location of retinal neurons and to the steadily increasing rate of intraocular surgical and pharmacological treatments applied to various eye diseases. Within few decades neuroprotection has developed from strongly contested approaches to being recognized and introduced as a potentially clinical application. One of the groups of putative substances for neuroprotection comprises alpha A- and alpha B-crystallins, which are types of heat-shock proteins and are considered to be molecular chaperones. The beta/gamma-crystallins form their own superfamily and are characterized as proteins with a distinct structure containing four Greek key motifs. Besides being abundant in the ocular lens, crystallins are also expressed in both the developing and mature retina. Crystallins are dramatically up-regulated in numerous retinal pathologies, including mechanical injury, ischemic insults, age-related macular degeneration, uveoretinitis, and diabetic retinopathy. Crystallins of the alpha family are thought to play a crucial role in retinal neuron survival and inflammation. Crystallins of the beta/gamma superfamily are also small proteins with a possible emerging role in retinal tissue remodeling and repair. One of the typical retinal diseases associated with crystallins is the experimental glaucomatous neuropathy that is characterized by their expression. Another typical retinal disease is the atrophy that occurs after mechanical injury to the optic nerve, which is associated with the need to regrow retinal axons. We have shown in regenerative models in vivo and in vitro that beta B2-crystallin actively supports the regenerative growth of cut retinal axons, thereby offering targets for neuroprotective and regenerative treatments. In this review we discuss the discovery that beta B2-crystallin is clearly up-regulated in the regenerating retina in vitro. beta B2-Crystallin is produced and secreted during axon elongation, while beta/gamma-crystallins promote axon growth both in vivo and in vitro by acting either directly by uptake into cells, or indirectly by enhancing the production of ciliary neurotrophic factor from astrocytes to synergistically promote axon regrowth. We also discuss methods to induce the continuous production of crystallins at the site of injury and repair based on the use of transfected neural progenitor cells. This review ultimately leads to the conclusion that the postinjury fate of neurons cannot be seen merely as inevitable, but instead should be regarded as a challenge to shaping the neuroprotective and regenerative conditions that promote cell survival and axon repair. (C) 2014 Elsevier Ltd. All rights reserved.