Axonal mitochondria degradation as the Achilles heel of retinal ganglion cells

 描述(由申请人提供)：Marsh-Armstrong实验室的长期目标是发现生物过程，这些过程有朝一日可能成为青光眼的治疗目标。最近，我们发现很大一部分线粒体并不是被视网膜神经节细胞本身降解的，而是传递给星形胶质细胞进行降解的。这种不同寻常的线粒体跨细胞降解模式，或称吞噬传递，更多发生在视神经头，而不是神经系统的任何其他部位。由于视神经头可能是青光眼的损伤部位，也可能是其他视神经萎缩的损伤部位，这是由于线粒体的特殊缺陷，我们认为视神经头线粒体的退化可能是视网膜神经节细胞的阿喀琉斯之踵，使它们容易受到各种疾病的影响，表现为轴突的节段性丢失。在目前的授权中，我们建议检验这一假设的几个预测。首先，我们建议确定在诱导性严重线粒体损伤、显性视差和青光眼的啮齿动物模型中，轴突线粒体是否比胞体内的线粒体更容易受到影响。其次，我们建议描绘负责轴突线粒体降解的视神经头的分子机制，并表明它确实对维持健康的视网膜神经节细胞至关重要。第三，我们将确定最近被其他人证明与线粒体退化有关的青光眼基因optineurin是否在视神经头特异地作用于促进受损轴突线粒体的退化。为了检验这一无可否认的大胆假设，我们开发了几个新工具，这些工具将适用于其他与线粒体基础生物学相关的研究，以及线粒体在各种疾病中是如何受到影响的。如果实验证明提出的假说在很大程度上是正确的，它将显著背离目前关于青光眼轴突丢失如何发生的观点，这将对有朝一日如何诊断和治疗青光眼具有重要意义。即使这一假设被实验证明是错误的，它仍然将对视网膜神经节细胞的生物学和病理学产生宝贵的见解。

 DESCRIPTION (provided by applicant): The long‐term goal of the Marsh‐Armstrong laboratory is to discover biological processes that may someday become treatment targets in Glaucoma. Recently, we discovered that a large fraction of mitochondria are not degraded by the retinal ganglion cells themselves, but rather passed onto astrocytes for degradation. This unusual mode of transcellular degradation of mitochondria, or transmitophagy, occurs more at the optic nerve head than anywhere else in the nervous system. Since the optic nerve head is the likely site of injury in Glaucoma, and a possible site of injury in other optic atrophies that re due to specific deficits in mitochondria, we propose that the degradation of mitochondria at the optic nerve head may be the Achilles' heel of retinal ganglion cells, making them vulnerable to various diseases that manifest as sectorial loss of axons. In the current grant, we propose to test several predictions of this hypothesis. First, we propose to determine whether in rodent models of induced severe mitochondrial impairment, dominant optic atropy and glaucoma, the axonal mitochondria are more susceptible than the mitochondria that are in the soma. Second, we propose to delineate the molecular machinery at the optic nerve head that is responsible for the degradation of axonal mitochondria, and to show that it is indeed critical for the maintenance of healthy retinal ganglion cells. Thirdly, we will determine whether a glaucoma gene, Optineurin, which has been recently shown by others to be involved in mitochondria degradation, acts specifically at the optic nerve head to facilitate the degradation of damaged axonal mitochondria. To test what is admittedly a bold hypothesis, we have developed several new tools that will be applicable to other studies relating to the basic biology of mitochondria, and of how mitochondria are affected in varied diseases. Should the experiments demonstrate that the proposed hypothesis is largely correct, it would represent a significant departure from current views of how glaucomatous axonal loss occurs, and this would have important implications as to how glaucoma might one day be diagnosed and treated. Even if the hypothesis is proven incorrect by the experiments, it will still yield invaluable insight into the biology and pathology of retinal ganglion cells.