Akopian Abram, Kumar Sandeep, Ramakrishnan Hariharasubramanian, Roy Kaushambi, Viswanathan Suresh, Bloomfield Stewart A
J Clin Invest. 2017 Jun 30;127(7):2647-2661. doi: 10.1172/JCI91948. Epub 2017 Jun 12.
The progressive death of retinal ganglion cells and resulting visual deficits are hallmarks of glaucoma, but the underlying mechanisms remain unclear. In many neurodegenerative diseases, cell death induced by primary insult is followed by a wave of secondary loss. Gap junctions (GJs), intercellular channels composed of subunit connexins, can play a major role in secondary cell death by forming conduits through which toxic molecules from dying cells pass to and injure coupled neighbors. Here we have shown that pharmacological blockade of GJs or genetic ablation of connexin 36 (Cx36) subunits, which are highly expressed by retinal neurons, markedly reduced loss of neurons and optic nerve axons in a mouse model of glaucoma. Further, functional parameters that are negatively affected in glaucoma, including the electroretinogram, visual evoked potential, visual spatial acuity, and contrast sensitivity, were maintained at control levels when Cx36 was ablated. Neuronal GJs may thus represent potential therapeutic targets to prevent the progressive neurodegeneration and visual impairment associated with glaucoma.
视网膜神经节细胞的渐进性死亡及由此导致的视觉缺陷是青光眼的特征，但潜在机制仍不清楚。在许多神经退行性疾病中，原发性损伤诱导的细胞死亡之后会出现一波继发性损失。间隙连接（GJ）是由连接蛋白亚基组成的细胞间通道，可通过形成管道，使来自死亡细胞的有毒分子传递并损伤相邻的耦合细胞，在继发性细胞死亡中起主要作用。在这里，我们已经表明，对GJ进行药理学阻断或对视网膜神经元高度表达的连接蛋白36（Cx36）亚基进行基因消融，可在青光眼小鼠模型中显著减少神经元和视神经轴突的损失。此外，当Cx36被消融时，在青光眼中受到负面影响的功能参数，包括视网膜电图、视觉诱发电位、视觉空间敏锐度和对比敏感度，都维持在对照水平。因此，神经元GJ可能是预防与青光眼相关的进行性神经退行性变和视觉损害的潜在治疗靶点。
