Hartopp Naomi, Lau Dawn H W, Martin-Guerrero Sandra M, Markovinovic Andrea, Mórotz Gábor M, Greig Jenny, Glennon Elizabeth B, Troakes Claire, Gomez-Suaga Patricia, Noble Wendy, Miller Christopher C J
Department of Basic and Clinical Neuroscience. Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
Front Cell Dev Biol. 2022 Aug 16;10:950767. doi: 10.3389/fcell.2022.950767. eCollection 2022.
Signaling between the endoplasmic reticulum (ER) and mitochondria regulates many neuronal functions that are perturbed in amyotrophic lateral sclerosis (ALS) and perturbation to ER-mitochondria signaling is seen in cell and transgenic models of ALS. However, there is currently little evidence that ER-mitochondria signaling is altered in human ALS. ER-mitochondria signaling is mediated by interactions between the integral ER protein VAPB and the outer mitochondrial membrane protein PTPIP51 which act to recruit and "tether" regions of ER to the mitochondrial surface. The VAPB-PTPI51 tethers are now known to regulate a number of ER-mitochondria signaling functions. These include delivery of Ca from ER stores to mitochondria, mitochondrial ATP production, autophagy and synaptic activity. Here we investigate the VAPB-PTPIP51 tethers in post-mortem control and ALS spinal cords. We show that VAPB protein levels are reduced in ALS. Proximity ligation assays were then used to quantify the VAPB-PTPIP51 interaction in spinal cord motor neurons in control and ALS cases. These studies revealed that the VAPB-PTPIP51 tethers are disrupted in ALS. Thus, we identify a new pathogenic event in post-mortem ALS.
内质网（ER）与线粒体之间的信号传导调节着许多在肌萎缩侧索硬化症（ALS）中受到干扰的神经元功能，并且在ALS的细胞和转基因模型中可以看到内质网-线粒体信号传导受到干扰。然而，目前几乎没有证据表明内质网-线粒体信号传导在人类ALS中发生改变。内质网-线粒体信号传导是由内质网整合蛋白VAPB与线粒体外膜蛋白PTPIP51之间的相互作用介导的，这些相互作用起到将内质网区域招募并“拴系”到线粒体表面的作用。现在已知VAPB-PTPI51拴系调节许多内质网-线粒体信号传导功能。这些功能包括将内质网储存的钙输送到线粒体、线粒体ATP生成、自噬和突触活动。在这里，我们研究了死后对照和ALS脊髓中的VAPB-PTPIP51拴系。我们发现ALS中VAPB蛋白水平降低。然后使用邻近连接分析来量化对照和ALS病例中脊髓运动神经元中VAPB-PTPIP51的相互作用。这些研究表明，ALS中VAPB-PTPIP51拴系被破坏。因此，我们在死后ALS中发现了一个新的致病事件。
