Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Institute of Reproductive Health, Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Cell Death Dis. 2021 Dec 11;12(12):1149. doi: 10.1038/s41419-021-04445-6.
Glaucoma is a leading cause of irreversible blindness worldwide and is characterized by progressive optic nerve degeneration and retinal ganglion cell loss. Axonal transport deficits have been demonstrated to be the earliest crucial pathophysiological changes underlying axonal degeneration in glaucoma. Here, we explored the role of the tetraspanin superfamily member CD82 in an acute ocular hypertension model. We found a transient downregulation of CD82 after acute IOP elevation, with parallel emergence of axonal transport deficits. The overexpression of CD82 with an AAV2/9 vector in the mouse retina improved optic nerve axonal transport and ameliorated subsequent axon degeneration. Moreover, the CD82 overexpression stimulated optic nerve regeneration and restored vision in a mouse optic nerve crush model. CD82 exerted a protective effect through the upregulation of TRAF2, which is an E3 ubiquitin ligase, and activated mTORC1 through K63-linked ubiquitylation and intracellular repositioning of Raptor. Therefore, our study offers deeper insight into the tetraspanin superfamily and demonstrates a potential neuroprotective strategy in glaucoma treatment.
青光眼是全球范围内导致不可逆性失明的主要原因，其特征为进行性视神经退行性变和视网膜神经节细胞丧失。轴突运输缺陷已被证明是青光眼轴突退行性变的最早关键病理生理变化。在这里，我们探讨了四跨膜蛋白超家族成员 CD82 在急性眼压升高模型中的作用。我们发现急性眼压升高后 CD82 短暂下调，同时出现轴突运输缺陷。用 AAV2/9 载体在小鼠视网膜中过表达 CD82 可改善视神经轴突运输，并减轻随后的轴突退化。此外，CD82 的过表达通过上调 TRAF2（一种 E3 泛素连接酶）刺激视神经再生，并在小鼠视神经挤压模型中恢复视力。CD82 通过 K63 连接泛素化和 Raptor 的细胞内重定位来激活 mTORC1，从而发挥保护作用。因此，我们的研究深入了解了四跨膜蛋白超家族，并展示了一种治疗青光眼的潜在神经保护策略。
