Neurotoxicity of Reactive Astrocyte-secreted Lipids in Neurodegenerative Disease

项目摘要 青光眼是一种以视网膜神经节细胞神经元死亡为特征的神经退行性疾病 视网膜中的视网膜节细胞（RGC），通常是眼内压长期升高的结果。这种细胞死亡导致 视力下降，最终失明。虽然神经胶质和免疫反应与 青光眼，很少了解他们的潜在致病作用，在视力丧失。反应性星形胶质细胞 越来越多地显示出在广泛的神经退行性疾病的传统病理学读数之前出现 疾病，包括青光眼。我们和其他人报告的一个反应性星形胶质细胞亚群是pupulmonary 神经毒性这些神经毒性反应性星形胶质细胞存在于人类神经退行性变的区域， 来自患有多种衰老疾病的患者的死后组织，以及在急性损伤后的视网膜中， RGC轴突和青光眼珠阻塞模型中的慢性视网膜变性。防止形成 的神经毒性反应性星形胶质细胞防止神经元死亡，和备用神经元是电生理 功能性的，因此在损伤后和疾病中仍然具有潜在的再生价值。 我们现在报道，这些反应性星形胶质细胞分泌一种有效的神经毒性脂质，特别是长链游离脂肪酸， 酸，其在体外和体内均诱导神经元死亡。阻断参与产生有毒物质的酶 星形胶质细胞中的脂质Elovl 1保留了神经元数量。总之，这些发现突出了一个反应性的子集， 星形胶质细胞作为眼睛慢性神经退行性疾病中RGC死亡的驱动因素。在这里我们将调查 反应性星形胶质细胞衍生的毒性脂质的作用，以确定反应性星形胶质细胞的时间和机制 在对眼睛的急性和慢性损伤期间，在驱动视网膜中的RGC胞体的死亡中。我们将重点关注三个 广泛的研究问题：PERK-ATF 3通路是星形胶质细胞驱动神经元细胞死亡所必需的吗？ 有毒脂质阻断神经毒性反应性星形胶质细胞能保护神经元功能和视力吗 在青光眼的小鼠模型中那么，神经元易感性的要求是什么呢？ 星形胶质细胞诱导的细胞死亡我们将使用小鼠模型确定视神经轴突的维持 缺乏反应性星形胶质细胞释放的神经毒性脂质，并研究视觉功能的变化， 使用野生型和毒性脂质缺乏小鼠在昏迷小鼠中的敏锐度，以确定是否靶向反应性 星形胶质细胞可以保护视力。我们还将研究PERK-ATF 3介导的 脂调亡途径--反应性星形胶质细胞分泌毒性脂质驱动细胞死亡的假定机制 神经元 本提案将探讨一种新的方法来维持视力青光眼。它将提供第一个 星形胶质细胞反应性、RGC健康、视力和丘脑突触连接之间的联系。

PROJECT SUMMARY Glaucoma is a neurodegenerative disease of aging that features the death of retinal ganglion cell neurons (RGCs) in the retina, often as a result of prolonged increases in intraocular pressure. This cell death leads to a decrease in visual acuity and ultimately blindness. While glial and immune responses have been associated with glaucoma, little understood about their potential causative role in loss of vision. Reactive astrocytes are increasingly shown to appear well before traditional pathological readouts of a wide range of neurodegenerative diseases, including glaucoma. One subset of reactive astrocytes reported by us and others as putatively neurotoxic. These neurotoxic reactive astrocytes are present in regions of neurodegeneration in human postmortem tissue from patients with multiple diseases of aging, as well as in the retina following acute injury to RGC axons and in a chronic retinal degeneration in a bead occlusion model of glaucoma. Preventing formation of neurotoxic reactive astrocytes prevents death of neurons, and spared neurons are electrophysiologically functional and thus still have potential value for regeneration following injury and in disease. We now report that these reactive astrocytes secrete a potent neurotoxic lipid, specifically long-chain free fatty acids, that induce death of neurons, both in vitro and in vivo. Block of the enzyme involved in production of toxic lipids, Elovl1, in astrocytes preserves neuron numbers. Together, these findings highlight a subset of reactive astrocytes as drivers of RGC death in a chronic neurodegenerative disease of the eye. Here we will investigate the role of reactive astrocyte-derived toxic lipids to determine the timing and mechanism of reactive astrocytes in driving death of RGC somas in the retina, during acute and chronic injury to the eye. We will focus on three broad research questions: is the PERK-ATF3 pathway required to drive neuron cell death by astrocyte toxic lipids? Does blocking neurotoxic reactive astrocytes preserve neuronal function and visual acuity in a mouse model of glaucoma? And what is the requirement for neuronal susceptibility prior to astrocyte-induced cell death? We will determine maintenance of optic nerve axons using a mouse model deficient for neurotoxic lipids released by reactive astrocytes in combination with investigating changes in visual acuity in glaucomatous mice using both wildtype and toxic lipid-deficient mice to determine if targeting reactive astrocytes can preserve vision. We will also investigate individual components of the PERK-ATF3 mediated lipoapoptosis pathway – a putative mechanism by which reactive astrocyte secreted toxic lipids drive death of neurons. This proposal will investigate a novel approach to maintain vision during glaucoma. It will provide for the first time a connection between astrocyte reactivity, RGC health, visual acuity, and thalamic synaptic connections.