Mfn2 ablation causes an oxidative stress response and eventual neuronal death in the hippocampus and cortex.
Mfn2 ablation causes an oxidative stress response and eventual neuronal death in the hippocampus and cortex.
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Mfn2 消融会导致海马和皮质中的氧化应激反应并最终导致神经元死亡
DOI：
10.1186/s13024-018-0238-8
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发表时间：
2018-02-01
影响因子：
15.1
通讯作者：
Zhu X
中科院分区：
文献类型：
--
作者：
Jiang S;Nandy P;Wang W;Ma X;Hsia J;Wang C;Wang Z;Niu M;Siedlak SL;Torres S;Fujioka H;Xu Y;Lee HG;Perry G;Liu J;Zhu X
研究背景线粒体是负责能量代谢的细胞器，对神经元的功能和存活有直接影响。线粒体异常在阿尔茨海默病（AD）中已得到很好的表征。据信，由于受损的分裂和融合平衡，线粒体碎片化可能导致线粒体功能障碍，这是AD中神经退行性变化的许多方面的基础。线粒体分裂和融合蛋白在维持这些重要细胞器的健康和功能方面发挥着重要作用。Mitofusion 2（Mfn 2）是一种调节线粒体融合的蛋白质，其中突变导致神经系统疾病MethodsTo检查受损的线粒体分裂/融合平衡是否以及如何导致AD中的神经变性，我们开发了一种转基因小鼠模型，其使用CAMK II启动子敲除海马和皮质中的神经元Mfn 2，AD明显影响的区域。结果这些小鼠神经元的电子显微镜照片显示线粒体肿胀、嵴损伤和线粒体膜异常。随着时间的推移，Mfn 2 cKO模型证明了神经变性通过线粒体形态学变化、氧化应激反应、炎性变化和树突中MAP 2的丢失而进展，导致严重和选择性神经元死亡。在该模型中，海马CA 1区神经元较早受到影响，并导致几乎完全丧失，而在皮质中，进行性神经元死亡与皮质大小减小相关。我们的研究结果表明，受损的线粒体分裂和融合平衡可导致海马和皮层中AD的许多神经退行性变化和最终的神经元损失，这使其成为治疗策略的潜在目标。对于AD。
BackgroundMitochondria are the organelles responsible for energy metabolism and have a direct impact on neuronal function and survival. Mitochondrial abnormalities have been well characterized in Alzheimer Disease (AD). It is believed that mitochondrial fragmentation, due to impaired fission and fusion balance, likely causes mitochondrial dysfunction that underlies many aspects of neurodegenerative changes in AD. Mitochondrial fission and fusion proteins play a major role in maintaining the health and function of these important organelles. Mitofusion 2 (Mfn2) is one such protein that regulates mitochondrial fusion in which mutations lead to the neurological disease.MethodsTo examine whether and how impaired mitochondrial fission/fusion balance causes neurodegeneration in AD, we developed a transgenic mouse model using the CAMKII promoter to knockout neuronal Mfn2 in the hippocampus and cortex, areas significantly affected in AD.ResultsElectron micrographs of neurons from these mice show swollen mitochondria with cristae damage and mitochondria membrane abnormalities. Over time the Mfn2 cKO model demonstrates a progression of neurodegeneration via mitochondrial morphological changes, oxidative stress response, inflammatory changes, and loss of MAP2 in dendrites, leading to severe and selective neuronal death. In this model, hippocampal CA1 neurons were affected earlier and resulted in nearly total loss, while in the cortex, progressive neuronal death was associated with decreased cortical size.ConclusionsOverall, our findings indicate that impaired mitochondrial fission and fusion balance can cause many of the neurodegenerative changes and eventual neuron loss that characterize AD in the hippocampus and cortex which makes it a potential target for treatment strategies for AD.
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影响因子：
64.5
作者：
Chen H;Vermulst M;Wang YE;Chomyn A;Prolla TA;McCaffery JM;Chan DC
通讯作者：
Chan DC
DOI：
10.1097/nen.0b013e318248e614
发表时间：
2012-03
影响因子：
3.2
作者：
Nunomura A;Tamaoki T;Motohashi N;Nakamura M;McKeel DW Jr;Tabaton M;Lee HG;Smith MA;Perry G;Zhu X
通讯作者：
Zhu X
DOI：
10.3233/jad-2010-100564
发表时间：
2010
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Manczak M;Mao P;Calkins MJ;Cornea A;Reddy AP;Murphy MP;Szeto HH;Park B;Reddy PH
通讯作者：
Reddy PH
DOI：
10.1073/pnas.1006586107
发表时间：
2010-10-26
影响因子：
11.1
作者：
Du, Heng;Guo, Lan;Yan, Shirley ShiDu
通讯作者：
Yan, Shirley ShiDu
影响因子：
4.8
作者：
Fifre, A;Sponne, I;Pillot, T
通讯作者：
Pillot, T