CRMP2 Participates in Regulating Mitochondrial Morphology and Motility in Alzheimer's Disease.
CRMP2 Participates in Regulating Mitochondrial Morphology and Motility in Alzheimer's Disease.
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线粒体生物能量学和动力学（线粒体形态和运动性的改变）在神经元对健康和疾病中不同能量需求的反应中起着关键作用。在阿尔茨海默病（AD）中，线粒体经历过度分裂并且变得不太能动。导致这些变化的机制尚不完全清楚。在这里，我们发现，阿尔茨海默病中的阿尔茨海默病反应介导蛋白2（CRMP 2）是过度磷酸化的，并伴随着CRMP 2与Drp 1，Miro 2和Mitofusin 2的相互作用减少，这些蛋白质参与调节线粒体形态和运动。CRMP 2在AD患者的死后脑组织、脑裂解物和来自双转基因APP/PS1小鼠（AD小鼠模型）的培养的皮层神经元中过度磷酸化。CRMP 2的过度磷酸化和从其结合伙伴的解离与增加的Drp 1招募到线粒体，增强线粒体碎片化，并减少线粒体运动。（S）-拉考沙胺（（S）-LCM）是一种与CRMP 2结合的小分子，可降低CRMP 2在Ser 522和Thr 509/514的磷酸化，恢复CRMP 2与Miro 2、Drp 1和Mitofusin 2的相互作用。这是通过减少Drp 1募集到线粒体，减少线粒体碎片，并提高细胞器的运动性。此外，（S）-LCM保护培养的皮质AD神经元免于细胞死亡。因此，我们的数据表明，CRMP 2，在磷酸化依赖的方式，参与线粒体形态和运动的调节，并调节AD神经元的存活。
Mitochondrial bioenergetics and dynamics (alterations in morphology and motility of mitochondria) play critical roles in neuronal reactions to varying energy requirements in health and disease. In Alzheimer’s disease (AD), mitochondria undergo excessive fission and become less motile. The mechanisms leading to these alterations are not completely clear. Here, we show that collapsin response mediator protein 2 (CRMP2) is hyperphosphorylated in AD and that is accompanied by a decreased interaction of CRMP2 with Drp1, Miro 2, and Mitofusin 2, which are proteins involved in regulating mitochondrial morphology and motility. CRMP2 was hyperphosphorylated in postmortem brain tissues of AD patients, in brain lysates, and in cultured cortical neurons from the double transgenic APP/PS1 mice, an AD mouse model. CRMP2 hyperphosphorylation and dissociation from its binding partners correlated with increased Drp1 recruitment to mitochondria, augmented mitochondrial fragmentation, and reduced mitochondrial motility. (S)-lacosamide ((S)-LCM), a small molecule that binds to CRMP2, decreased its phosphorylation at Ser 522 and Thr 509/514, and restored CRMP2′s interaction with Miro 2, Drp1, and Mitofusin 2. This was paralleled by decreased Drp1 recruitment to mitochondria, diminished mitochondrial fragmentation, and improved motility of the organelles. Additionally, (S)-LCM-protected cultured cortical AD neurons from cell death. Thus, our data suggest that CRMP2, in a phosphorylation-dependent manner, participates in the regulation of mitochondrial morphology and motility, and modulates neuronal survival in AD.
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影响因子：
3.5
作者：
Chen H;Chan DC
通讯作者：
Chan DC
DOI：
10.2174/138955708786369582
发表时间：
2008-11
期刊：
Mini reviews in medicinal chemistry
影响因子：
--
作者：
Aliev G;Obrenovich ME;Reddy VP;Shenk JC;Moreira PI;Nunomura A;Zhu X;Smith MA;Perry G
通讯作者：
Perry G
影响因子：
2.1
作者：
Cai, Zhiyou;Zhao, Yu;Zhao, Bin
通讯作者：
Zhao, Bin
影响因子：
82.9
作者：
Du, Heng;Guo, Lan;Fang, Fang;Chen, Doris;Sosunov, Alexander A.;McKhann, Guy M.;Yan, Yilin;Wang, Chunyu;Zhang, Hong;Molkentin, Jeffery D.;Gunn-Moore, Frank J.;Vonsattel, Jean Paul;Arancio, Ottavio;Chen, John Xi;Du Yan, Shi
通讯作者：
Du Yan, Shi
影响因子：
5.6
作者：
Comes G;Manso Y;Escrig A;Fernandez-Gayol O;Sanchis P;Molinero A;Giralt M;Carrasco J;Hidalgo J
通讯作者：
Hidalgo J