Liu Dong, Webber Hannah C, Bian Fuyun, Xu Yangfan, Prakash Manjari, Feng Xue, Yang Ming, Yang Hang, You In-Jee, Li Liang, Liu Liping, Liu Pingting, Huang Haoliang, Chang Chien-Yi, Liu Liang, Shah Sahil H, La Torre Anna, Welsbie Derek S, Sun Yang, Duan Xin, Goldberg Jeffrey Louis, Braun Marcus, Lansky Zdenek, Hu Yang
Spencer Center for Vision Research, Department of Ophthalmology, Byers Eye Institute at Stanford University School of Medicine, Palo Alto, CA, USA.
Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University; NHC Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences; Shanghai Research Center of Ophthalmology and Optometry, Shanghai, P.R. China.
Nat Commun. 2025 Feb 20;16(1):1789. doi: 10.1038/s41467-025-57135-8.
Optineurin (OPTN) mutations are linked to amyotrophic lateral sclerosis (ALS) and normal tension glaucoma (NTG), but a relevant animal model is lacking, and the molecular mechanisms underlying neurodegeneration are unknown. We find that OPTN C-terminus truncation (OPTN∆C) causes late-onset neurodegeneration of retinal ganglion cells (RGCs), optic nerve (ON), and spinal cord motor neurons, preceded by a decrease of axonal mitochondria in mice. We discover that OPTN directly interacts with both microtubules and the mitochondrial transport complex TRAK1/KIF5B, stabilizing them for proper anterograde axonal mitochondrial transport, in a C-terminus dependent manner. Furthermore, overexpressing OPTN/TRAK1/KIF5B prevents not only OPTN truncation-induced, but also ocular hypertension-induced neurodegeneration, and promotes robust ON regeneration. Therefore, in addition to generating animal models for NTG and ALS, our results establish OPTN as a facilitator of the microtubule-dependent mitochondrial transport necessary for adequate axonal mitochondria delivery, and its loss as the likely molecular mechanism of neurodegeneration.
视紫质（OPTN）突变与肌萎缩侧索硬化症（ALS）和正常眼压性青光眼（NTG）有关，但缺乏相关动物模型，神经退行性变的分子机制也尚不清楚。我们发现，视紫质C末端截短（OPTN∆C）会导致小鼠视网膜神经节细胞（RGC）、视神经（ON）和脊髓运动神经元出现迟发性神经退行性变，在此之前轴突线粒体数量会减少。我们发现，视紫质直接与微管以及线粒体运输复合体TRAK1/KIF5B相互作用，以C末端依赖的方式稳定它们，从而实现轴突线粒体的正常顺向运输。此外，过表达视紫质/TRAK1/KIF5B不仅能预防视紫质截短诱导的神经退行性变，还能预防高眼压诱导产生的神经退行性变，并促进视神经的强劲再生。因此，除了为正常眼压性青光眼和肌萎缩侧索硬化症建立动物模型外，我们的研究结果还证实，视紫质是轴突线粒体充分运输所需的微管依赖性线粒体运输的促进因子，其缺失可能是神经退行性变的分子机制。
