Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85721, USA.
Cells. 2021 Nov 15;10(11):3172. doi: 10.3390/cells10113172.
Mitochondrial morphology and motility (mitochondrial dynamics) play a major role in the proper functioning of distant synapses. In Huntington's disease (HD), mitochondria become fragmented and less motile, but the mechanisms leading to these changes are not clear. Here, we found that collapsin response mediator protein 2 (CRMP2) interacted with Drp1 and Miro 2, proteins involved in regulating mitochondrial dynamics. CRMP2 interaction with these proteins inversely correlated with CRMP2 phosphorylation. CRMP2 was hyperphosphorylated in postmortem brain tissues of HD patients, in human neurons derived from induced pluripotent stem cells from HD patients, and in cultured striatal neurons from HD mouse model YAC128. At the same time, CRMP2 interaction with Drp1 and Miro 2 was diminished in HD neurons. The CRMP2 hyperphosphorylation and dissociation from Drp1 and Miro 2 correlated with increased fission and suppressed motility. (S)-lacosamide ((S)-LCM), a small molecule that binds to CRMP2, decreased its phosphorylation at Thr 509/514 and Ser 522 and rescued CRMP2's interaction with Drp1 and Miro 2. This was accompanied by reduced mitochondrial fission and enhanced mitochondrial motility. Additionally, (S)-LCM exerted a neuroprotective effect in YAC128 cultured neurons. Thus, our data suggest that CRMP2 may regulate mitochondrial dynamics in a phosphorylation-dependent manner and modulate neuronal survival in HD.
线粒体形态和运动（线粒体动力学）在远距离突触的正常功能中起着重要作用。在亨廷顿病（HD）中，线粒体变得碎片化，运动能力降低，但导致这些变化的机制尚不清楚。在这里，我们发现 collapsin 反应介质蛋白 2（CRMP2）与 Drp1 和 Miro 2 相互作用，这两种蛋白参与调节线粒体动力学。CRMP2 与这些蛋白的相互作用与 CRMP2 的磷酸化呈负相关。HD 患者死后脑组织、HD 患者诱导多能干细胞衍生的人神经元以及 HD 小鼠模型 YAC128 培养的纹状体神经元中，CRMP2 过度磷酸化。与此同时，HD 神经元中 CRMP2 与 Drp1 和 Miro 2 的相互作用减少。CRMP2 的过度磷酸化和与 Drp1 和 Miro 2 的解离与分裂增加和运动抑制有关。（S）-拉科酰胺（（S）-LCM），一种与 CRMP2 结合的小分子，可降低其 Thr 509/514 和 Ser 522 的磷酸化，并挽救 CRMP2 与 Drp1 和 Miro 2 的相互作用。这伴随着线粒体分裂减少和线粒体运动增强。此外，（S）-LCM 在 YAC128 培养的神经元中发挥神经保护作用。因此，我们的数据表明，CRMP2 可能以磷酸化依赖的方式调节线粒体动力学，并调节 HD 中的神经元存活。
