OPA1 Mutation and Retinal Ganglion Cell Degeneration

描述（由申请人提供）：常染色体显性视神经萎缩（DOA）是最常见的遗传性视神经病变，导致幼儿中心视力丧失。在DOA中，视网膜神经节细胞死亡，并且视神经通过未知的机制退化。不幸的是，没有治疗或治愈DOA。最近的进展确定了DOA中突变的基因。该基因定位于染色体3q 28，被称为视神经萎缩1型（Optic Atrophy Type 1，OPA 1）。有趣的是，OPA 1编码一种线粒体蛋白。OPA 1的确切功能尚不清楚。然而，在其酵母同源物中，OPA 1可以促进线粒体融合并维持线粒体网络和线粒体DNA（mtDNA）。OPA 1是动力蛋白相关的GT3，可以作为机械酶或调节性GT3。该项目的目标是确定DOA中视网膜神经节细胞和视神经变性的机制。 具体的问题是：（1）OPA 1突变是否会导致线粒体网络的破坏、线粒体DNA的缺失和线粒体超微结构的异常？(2)OPA 1失活是否会导致呼吸障碍、ATP减少、线粒体膜电位降低、自由基增加以及对UV或NMDA/NO诱导的细胞死亡的敏化？(3)OPA 1的生物物理和结构特征是什么？ 在这项研究中，视网膜神经节细胞将使用“跨学科”的方法进行研究，包括三维成像，电子断层扫描，细胞生物学，分子遗传学和生物能量学。此外，生物信息学和结构生物学将被用来解开OPA 1的功能。 本研究将首次对OPA 1及其突变进行详细的细胞、分子、生化和结构分析。本研究结果可能揭示了DOA视网膜神经节细胞死亡的机制。重要的是，在这里获得的见解可能为新疗法奠定基础，以对抗DOA视力丧失。

DESCRIPTION (provided by applicant): Autosomal Dominant Optic Atrophy (DOA) is the most common hereditary form of optic neuropathy, leading to central vision loss in young children. In DOA retinal ganglion cells die and the optic nerve degenerates by an unknown mechanism. Unfortunately, there is no treatment or cure for DOA. Recent advances identified the gene that is mutated in DOA. The gene maps to chromosome 3q28 and is called Optic Atrophy Type 1 (OPA1). Intriguingly, OPA1 encodes a mitochondrial protein. The precise function of OPA1 remains unclear. However, in its yeast homologue, OPA1 may promote mitochondrial fusion and maintain the mitochondrial network and the mitochondrial DNA (mtDNA). OPA1 is a dynamin-related GTPase and may act either as a mechano-enzyme or a regulatory GTPase. The goal of this project is to identify the mechanism underlying retinal ganglion cell and optic nerve degeneration in DOA. The specific questions that will be addressed here are: (1) Do OPA1 mutations lead to breakdown of the mitochondrial network, mtDNA depletion, and abnormal mitochondrial ultrastructure? (2) Does OPA1 inactivation result in respiratory deficits, decrease in ATP, decrease in mitochondrial membrane potential, increase in free radicals, and sensitization to UV- or NMDA/NO-induced cell death? (3) What are the biophysical and structural characteristics of OPA1? In this study retinal ganglion cells will be studied using "interdisciplinary" approaches including 3D imaging, electron tomography, cell biology, molecular genetics, and bioenergetics. In addition, bioinformatics and structure biology will be used to unravel the function of OPA1. This study will embark on the first detailed cellular, molecular, biochemical and structural analysis of OPA1 and its mutations. Results obtained here may reveal a mechanistic explanation for the retinal ganglion cell death in DOA. Importantly, insights gained here may set the foundation for new therapies to fight vision loss in DOA.