Optic nerve head synucleinopathy in glaucoma and the function of gamma-synuclein

描述（由申请人提供）：本申请的广泛长期目标是揭示青光眼中视网膜神经节细胞（RGC）变性的机制，以便能够设计基于神经保护的合理治疗干预措施。基于最近的数据显示青光眼动物模型产生了？-视网膜和视神经中的突触核蛋白类似于帕金森病和动物模型中由α-突触核蛋白组成的聚集体，这似乎可能是青光眼和帕金森病共享许多致病机制。拟议的研究旨在了解的性质和意义？青光眼动物模型中的突触核蛋白聚集体。有两个过程似乎与？突触核蛋白聚集在小鼠中，经历类似于肉瘤的变化。首先，尽管？突触核蛋白仅在RGC中正常表达，在青光眼动物模型中，在视神经乳头内有一个新鉴定的星形胶质细胞亚群，其含有？突触核蛋白聚集并上调与吞噬作用相关的途径。第二，？发现突触核蛋白聚集体与脂质细胞器（脂滴）相关，并且在青光眼动物模型中这些脂滴大量增加。实验的目的是确定是否有一个因果关系？突触核蛋白聚集体和这两种相关现象。独立地，他们将测试这些相关现象是否与青光眼进展有关。最后，由于动物模型并不总是反映人类疾病的变化，在这些动物模型中的关键发现，将在经证实的青光眼患者的视网膜和视神经中检查突触核蛋白聚集体、星形胶质细胞吞噬作用和脂滴形成。这些研究很可能会揭示突触核蛋白在健康和疾病中的作用。重要的是，在确定青光眼的关键病理机制，这是如此类似于在其他常见的神经退行性疾病中看到的，拟议的研究可能会彻底改变如何青光眼的研究，并在未来，治疗。 公共卫生相关性：很可能拟议中的关于？青光眼中的突触核蛋白将产生许多关于突触核蛋白在健康和疾病中如何起作用的新信息。最重要的是，拟议中的研究将彻底改变青光眼的研究和治疗方式，并且可能会在为所有神经退行性疾病中第二常见的青光眼患者提供神经保护治疗方面迈出一大步。

DESCRIPTION (provided by applicant): The broad long-term goal of this application is to uncover the mechanism of retinal ganglion cell (RGC) degeneration in glaucoma so as to be able to design rational therapeutic interventions based on neuroprotection. Based on recent data showing that glaucoma animal models develop aggregates of ?-synuclein in the retina and optic nerve similar to the aggregates composed of a-synuclein in Parkinson's disease and animal models, it appears likely the glaucoma and Parkinson's disease share many pathogenic mechanisms. The proposed studies aim to understand the nature and significance of the ?-synuclein aggregates in glaucoma animal models. There are two processes that appear to correlate with the development of the ?-synuclein aggregates in mice that undergo glaucoma-like changes. First, despite ?-synuclein being expressed normally only in RGC, in glaucoma animal models there are a newly-identified subset of astrocytes within the optic nerve head that contain ?-synuclein aggregates and upregulate a pathway that is linked to phagocytosis. Second, the ?-synuclein aggregates are found associated with a lipid organelle, the lipid droplet, and there is a large increase in these lipid droplets in the glaucoma animal models. The proposed experiment aim to determine whether there is a cause and effect relationship between the ?-synuclein aggregates and these two associated phenomena. Independently, they will test whether these associated phenomena have any relevance to glaucoma progression. Finally, since animal models do not always reflect changes in human diseases, key findings made in these animal models regarding ?-synuclein aggregates, astrocyte phagocytosis, and lipid droplet formation, will be examined in the retinas and optic nerves of verified glaucoma patients. It is likely that the proposed studies will shed much light onto how synucleins function in health and disease. Importantly, in identifying a key pathological mechanism in glaucoma that is so similar to those seen in other common neurodegenerative disorders, the proposed studies may revolutionize how glaucoma is studied and, in the future, treated. PUBLIC HEALTH RELEVANCE: It is likely that the proposed studies on the role of ?-synuclein in glaucoma will yield much new information about how synucleins function in health and disease. Most importantly, the proposed studies will revolutionize how glaucoma is studied and treated, and likely will be a large step forward in bringing neuroprotective therapies to those afflicted by this second most common of all neurodegenerative disorders, glaucoma.