The maintenance of complex dendritic arbors and synaptic transmission are processes that require a substantial amount of energy. Bioenergetic decline is a prominent feature of chronic neurodegenerative diseases, yet the signaling mechanisms that link energy stress with neuronal dysfunction are poorly understood. Recent work has implicated energy deficits in glaucoma, and retinal ganglion cell (RGC) dendritic pathology and synapse disassembly are key features of ocular hypertension damage. We show that adenosine monophosphate-activated protein kinase (AMPK), a conserved energy biosensor, is strongly activated in RGC from mice with ocular hypertension and patients with primary open angle glaucoma. Our data demonstrate that AMPK triggers RGC dendrite retraction and synapse elimination. We show that the harmful effect of AMPK is exerted through inhibition of the mammalian target of rapamycin complex 1 (mTORC1). Attenuation of AMPK activity restores mTORC1 function and rescues dendrites and synaptic contacts. Strikingly, AMPK depletion promotes recovery of light-evoked retinal responses, improves axonal transport, and extends RGC survival. This study identifies AMPK as a critical nexus between bioenergetic decline and RGC dysfunction during pressure-induced stress, and highlights the importance of targeting energy homeostasis in glaucoma and other neurodegenerative diseases.

中文翻译：

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AMPK 过度激活促进青光眼中的树突收缩、突触丧失和神经元功能障碍

维持复杂的树突乔木和突触传递是需要大量能量的过程。生物能量下降是慢性神经退行性疾病的一个突出特征，但将能量压力与神经元功能障碍联系起来的信号机制却知之甚少。最近的研究表明青光眼的能量不足，视网膜神经节细胞 (RGC) 树突状病理和突触解体是高眼压损伤的关键特征。我们发现腺苷一磷酸活化蛋白激酶 (AMPK) 是一种能量守恒的生物传感器，在患有高眼压症的小鼠和原发性开角型青光眼患者的 RGC 中被强烈激活。我们的数据表明 AMPK 触发 RGC 树突收缩和突触消除。我们表明 AMPK 的有害作用是通过抑制哺乳动物的雷帕霉素复合物 1 (mTORC1) 靶标来发挥的。AMPK 活性的减弱可恢复 mTORC1 功能并拯救树突和突触接触。引人注目的是，AMPK 耗竭促进了光诱发视网膜反应的恢复，改善了轴突运输，并延长了 RGC 的存活率。本研究将 AMPK 确定为压力引起的压力期间生物能量下降和 RGC 功能障碍之间的关键关系，并强调了在青光眼和其他神经退行性疾病中针对能量稳态的重要性。改善轴突运输，并延长 RGC 的存活率。本研究将 AMPK 确定为压力引起的压力期间生物能量下降和 RGC 功能障碍之间的关键关系，并强调了在青光眼和其他神经退行性疾病中针对能量稳态的重要性。改善轴突运输，并延长 RGC 的存活率。本研究将 AMPK 确定为压力引起的压力期间生物能量下降和 RGC 功能障碍之间的关键关系，并强调了在青光眼和其他神经退行性疾病中针对能量稳态的重要性。