Department of Ophthalmology and Vision Science, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
Key Laboratory of Myopia of State Health Ministry and Key Laboratory of Visual Impairment and Restoration of Shanghai, Shanghai, 20031, China.
Cell Death Dis. 2018 Jan 24;9(2):88. doi: 10.1038/s41419-017-0146-9.
Glaucoma is a leading cause of irreversible blindness and characterized by progressive damage of retinal ganglion cells (RGCs). Growing evidences have linked impaired mitophagy with neurodegenerative diseases, while the E3 ubiquitin ligase parkin may play a key role. However, the pathophysiological relationship between parkin and glaucoma remains largely unknown. Using chronic hypertensive glaucoma rats induced by translimbal laser photocoagulation, we show here that the protein level of parkin and its downstream optineurin proteins were increased in hypertensive retinas. The ratio of LC3-II to LC3-I, the number of mitophagosomes, and unhealthy mitochondria were increased in hypertensive optic nerves. Overexpression of parkin by viral vectors increased RGC survival in glaucomatous rats in vivo and under excitotoxicity in vitro. It also promoted optineurin expression and improved mitochondrial health. In parkin-overexpressed glaucomatous rats, the ratio of LC3-II to LC3-I, LAMP1 level, and the number of mitophagosomes in optic nerve were decreased at 3 days, yet increased at 2 weeks following intraocular pressure (IOP) elevation. These findings demonstrate that dysfunction of mitophagy exist in RGCs of glaucomatous rats. Overexpression of parkin exerted a significant protective effect on RGCs and partially restored dysfunction of mitophagy in response to cumulative IOP elevation.
青光眼是不可逆性失明的主要原因，其特征是视网膜神经节细胞（RGC）的进行性损伤。越来越多的证据表明，线粒体自噬功能障碍与神经退行性疾病有关，而 E3 泛素连接酶 parkin 可能发挥关键作用。然而，parkin 与青光眼之间的病理生理关系在很大程度上尚不清楚。我们使用经瞬目激光光凝诱导的慢性高血压青光眼大鼠，在此表明高血压视网膜中 parkin 及其下游 optineurin 蛋白的蛋白水平增加。高血压视神经中 LC3-II 与 LC3-I 的比值、自噬小体的数量和不健康的线粒体增加。病毒载体过表达 parkin 可增加体内青光眼大鼠和体外兴奋性毒性条件下 RGC 的存活。它还促进了 optineurin 的表达，改善了线粒体的健康。在过表达 parkin 的青光眼大鼠中，视神经中 LC3-II 与 LC3-I 的比值、LAMP1 水平和自噬小体的数量在眼压升高后 3 天降低，但在 2 周后增加。这些发现表明，青光眼大鼠的 RGC 中存在线粒体自噬功能障碍。过表达 parkin 对 RGC 具有显著的保护作用，并部分恢复了对累积眼压升高的线粒体自噬功能障碍。
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