AMPK hyperactivation promotes dendrite retraction, synaptic loss, and neuronal dysfunction in glaucoma.
AMPK hyperactivation promotes dendrite retraction, synaptic loss, and neuronal dysfunction in glaucoma.
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DOI：
10.1186/s13024-021-00466-z
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发表时间：
2021-06-29
影响因子：
15.1
通讯作者：
Di Polo A
中科院分区：
文献类型：
--
作者：
Belforte N;Agostinone J;Alarcon-Martinez L;Villafranca-Baughman D;Dotigny F;Cueva Vargas JL;Di Polo A
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显著特征，但将能量应激与神经元功能障碍联系起来的信号传导机制却知之甚少。最近的研究表明青光眼中存在能量缺乏，视网膜神经节细胞（RGC）树突病理学和突触解体是高眼压损害的关键特征。我们发现，腺苷一磷酸活化蛋白激酶（AMPK），一个保守的能量生物传感器，强烈激活RGC从小鼠高眼压症和原发性开角型青光眼患者。我们的数据表明，AMPK触发RGC树突收缩和突触消除。我们发现AMPK的有害作用是通过抑制雷帕霉素复合物1（mTORC 1）的哺乳动物靶蛋白来实现的。AMPK活性的减弱恢复mTORC 1功能并拯救树突和突触接触。引人注目的是，AMPK耗竭促进光诱发视网膜反应的恢复，改善轴突运输，并延长RGC存活。这项研究将AMPK确定为压力诱导应激期间生物能量下降和RGC功能障碍之间的关键联系，并强调了在青光眼和其他神经退行性疾病中靶向能量稳态的重要性。在线版本包含补充材料，可通过10.1186/s13024-021-00466-z获得。
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. The online version contains supplementary material available at 10.1186/s13024-021-00466-z.
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影响因子：
7.7
作者：
Houde VP;Brûlé S;Festuccia WT;Blanchard PG;Bellmann K;Deshaies Y;Marette A
通讯作者：
Marette A
影响因子：
29
作者：
Gowans GJ;Hawley SA;Ross FA;Hardie DG
通讯作者：
Hardie DG
DOI：
10.1073/pnas.2014213117
发表时间：
2020-12-29
影响因子：
11.1
作者：
Harder JM;Guymer C;Wood JPM;Daskalaki E;Chidlow G;Zhang C;Balasubramanian R;Cardozo BH;Foxworth NE;Deering KE;Ouellette TB;Montgomery C;Wheelock CE;Casson RJ;Williams PA;John SWM
通讯作者：
John SWM
DOI：
10.1016/j.cbpb.2017.11.001
发表时间：
2018-10-01
影响因子：
2.2
作者：
Craig, Paul M.;Moyes, Christopher D.;LeMoine, Christophe M. R.
通讯作者：
LeMoine, Christophe M. R.
影响因子：
5.1
作者：
Compagnoni, Giacomo Monzio;Di Fonzo, Alessio;Corti, Stefania;Comi, Giacomo P.;Bresolin, Nereo;Masliah, Eliezer
通讯作者：
Masliah, Eliezer