Impaired Mitophagy Plays a Role in Denervation of Neuromuscular Junctions in ALS Mice.
Impaired Mitophagy Plays a Role in Denervation of Neuromuscular Junctions in ALS Mice.
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线粒体受损在ALS小鼠的神经肌肉连接处的神经上发挥作用。
DOI：
10.3389/fnins.2017.00473
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发表时间：
2017
影响因子：
4.3
通讯作者：
Nishimune H
中科院分区：
文献类型：
--
作者：
Rogers RS;Tungtur S;Tanaka T;Nadeau LL;Badawi Y;Wang H;Ni HM;Ding WX;Nishimune H
肌萎缩侧索硬化症（ALS）患者和动物模型中的运动神经元显示出神经末梢的变性，称为退变神经病。为了研究这种神经病变的机制，我们使用电子显微镜分析了SOD 1G 93 A小鼠的神经肌肉接头（NMJ）和运动神经元胞体。与野生型对照相比，SOD 1G 93 A小鼠的NMJ表现出显著更高数量的自噬体和退化的线粒体。在野生型小鼠和SOD 1G 93 A小鼠的NMJ突触前末端中鉴定出线粒体吞噬体。然而，线粒体吞噬体的数量在SOD 1G 93 A NMJ中没有显著增加，表明线粒体吞噬缺陷，即降解线粒体的自噬过程。与此一致，线粒体自噬所必需的蛋白质，p62/SQSTM 1，Bnip 3，Pink 1和Parkin在SOD 1G 93 A小鼠的运动神经元中下调。重要的是，SQSTM 1是家族性ALS患者中突变的基因之一。我们通过分析Pink 1和Parkin的双敲除小鼠来评估受损的线粒体自噬对运动神经元的影响，Pink 1和Parkin是两个负责感测去极化线粒体并将退化的线粒体传递到线粒体自噬体的基因。双基因敲除小鼠在4月龄时表现出NMJ变性，包括轴突肿胀和NMJ断裂。这些表型在同龄野生型对照小鼠中很少观察到。ATP合成酶β亚基在突触前末梢的蛋白水平增加，提示双基因敲除小鼠NMJ处线粒体的积累。重要的是，在双敲除小鼠中观察到NMJ去神经支配。这些数据表明，减少线粒体自噬功能的SOD 1G 93 A小鼠的运动神经元是导致ALS NMJ的变性的机制之一。
Motor neurons in amyotrophic lateral sclerosis (ALS) patients and animal models show degeneration from the nerve terminal, known as dying-back neuropathy. To investigate the mechanism underlying this neuropathy, we analyzed the neuromuscular junctions (NMJs) and motor neuron cell bodies in SOD1G93A mice using electron microscopy. NMJs of SOD1G93A mice exhibited significantly higher numbers of autophagosomes and degenerated mitochondria compared to wild-type controls. Mitophagosomes were identified in the NMJ presynaptic terminals of wild-type mice and SOD1G93A mice. However, the number of mitophagosomes did not increase significantly in SOD1G93A NMJs indicating a defect in mitophagy, the autophagic process to degrade mitochondria. Consistent with this, proteins essential for mitophagy, p62/SQSTM1, Bnip3, Pink1, and Parkin were down-regulated in motor neurons in SOD1G93A mice. Importantly, SQSTM1 is one of the genes mutated in familial ALS patients. We evaluated the effect of impaired mitophagy on motor neurons by analyzing the double knockout mice of Pink1 and Parkin, two genes responsible for sensing depolarized mitochondria and delivering degenerated mitochondria to mitophagosomes. The double knockout mice exhibited NMJ degeneration, including axon swelling and NMJ fragmentation at 4 months of age. These phenotypes were rarely observed in wild-type control mice of the same age. The protein level of ATP synthase β subunit increased in the NMJ presynaptic terminals, suggesting the accumulation of mitochondria at NMJs of the double knockout mice. Importantly, NMJ denervation was observed in the double knockout mice. These data suggest that the reduced mitophagy function in motor neurons of SOD1G93A mice is one of the mechanisms causing degeneration of ALS NMJs.
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影响因子：
5.3
作者：
Fischer, LR;Culver, DG;Glass, JD
通讯作者：
Glass, JD
DOI：
10.1083/jcb.201401070
发表时间：
2014-09-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ashrafi G;Schlehe JS;LaVoie MJ;Schwarz TL
通讯作者：
Schwarz TL
影响因子：
14.8
作者：
Barmada, Sami J.;Serio, Andrea;Arjun, Arpana;Bilican, Bilada;Daub, Aaron;Ando, D. Michael;Tsvetkov, Andrey;Pleiss, Michael;Li, Xingli;Peisach, Daniel;Shaw, Christopher;Chandran, Siddharthan;Finkbeiner, Steven
通讯作者：
Finkbeiner, Steven
影响因子：
7.8
作者：
Dobrowolny, Gabriella;Giacinti, Cristina;Pelosi, Laura;Nicoletti, Carmine;Winn, Nadine;Barberi, Laura;Molinaro, Mario;Rosenthal, Nadia;Musaro, Antonio
通讯作者：
Musaro, Antonio
DOI：
10.1164/ajrccm.161.3.9805008
发表时间：
2000-03-01
影响因子：
24.7
作者：
Arnulf, I;Similowski, T;Derenne, JP
通讯作者：
Derenne, JP