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可能有一天成为青光眼治疗靶点的生物学过程。最近，我们发现大部分线粒体不是由视网膜神经节细胞本身降解的，而是传递到星形胶质细胞进行降解。这种不寻常的线粒体跨细胞降解模式，或transmophagy，发生在视神经头比其他任何地方的神经系统。由于视神经乳头是青光眼的可能损伤部位，也是其他视神经萎缩的可能损伤部位，这些视神经萎缩是由于线粒体的特异性缺陷造成的，因此我们认为视神经乳头处线粒体的降解可能是视网膜神经节细胞的阿喀琉斯之踵，使它们容易受到表现为轴突扇形缺失的各种疾病的影响。在目前的补助金中，我们建议测试这一假设的几个预测。首先，我们建议确定是否在啮齿动物模型诱导严重的线粒体损伤，显性视神经萎缩和青光眼，轴突线粒体比线粒体中的索马更敏感。其次，我们建议描绘的视神经乳头的分子机制，负责轴突线粒体的降解，并表明它确实是至关重要的健康的视网膜神经节细胞的维护。第三，我们将确定是否青光眼基因，视神经磷酸酶，这是最近已被证明参与线粒体降解，特别是在视神经头，以促进受损轴突线粒体的降解。为了验证这个大胆的假设，我们开发了几种新的工具，这些工具将适用于与线粒体的基础生物学以及线粒体在各种疾病中如何受到影响有关的其他研究。如果实验证明所提出的假设在很大程度上是正确的，那么它将代表与当前关于青光眼轴突丢失如何发生的观点的重大偏离，并且这将对将来如何诊断和治疗青光眼具有重要意义。即使实验证明这一假设是不正确的，它仍然会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.