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

描述（由申请人提供）：本申请的长期目标是揭示青光眼视网膜神经节细胞（RGC）变性的机制，从而能够基于神经保护设计合理的治疗干预措施。根据最近的数据显示，青光眼动物模型产生了？视网膜和视神经中的-synuclein与帕金森病和动物模型中a-synuclein组成的聚集体相似，青光眼和帕金森病似乎有许多共同的致病机制。拟议的研究旨在了解？青光眼动物模型中的-synuclein聚集物。有两个过程似乎与？的发展有关。-synuclein在青光眼样变化的小鼠中聚集。首先，尽管？-synuclein仅在RGC中正常表达，在青光眼动物模型中，视神经头内新发现的星形胶质细胞亚群含有？-synuclein聚集并上调与吞噬作用相关的途径。第二，？-synuclein聚集体被发现与脂质细胞器，脂滴相关，并且在青光眼动物模型中这些脂滴大量增加。所提出的实验旨在确定两者之间是否存在因果关系。-synuclein聚集和这两种相关现象。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，在这些动物模型中得出的关键发现是关于？-synuclein聚集，星形胶质细胞吞噬和脂滴形成，将在证实的青光眼患者的视网膜和视神经中进行检查。很可能提出的研究将阐明突触核蛋白如何在健康和疾病中发挥作用。重要的是，在确定青光眼与其他常见神经退行性疾病相似的关键病理机制方面，拟议的研究可能会彻底改变青光眼的研究和未来的治疗方式。

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.