Targeting ER-Mitochondria Signaling as a Therapeutic Target for Frontotemporal Dementia and Related Amyotrophic Lateral Sclerosis.
Targeting ER-Mitochondria Signaling as a Therapeutic Target for Frontotemporal Dementia and Related Amyotrophic Lateral Sclerosis.
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DOI：
10.3389/fcell.2022.915931
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发表时间：
2022
影响因子：
5.5
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中科院分区：
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额颞叶痴呆(FTD)和肌萎缩侧索硬化症(ALS)是两种主要的神经退行性疾病。FTD是痴呆症的第二大常见原因，ALS是最常见的运动神经元病。现在已知这些疾病是有关联的。FTD或ALS尚无治愈或有效的治疗方法，因此需要新的治疗干预靶点，但FTD/ALS中大量的生理过程受损阻碍了这一目标的实现。其中许多受损的功能现在被认为是通过内质网(ER)和线粒体之间的信号来调节的。这种信号是由“拴系”蛋白介导的，这些蛋白负责将内质网招募到线粒体。与FTD/ALS密切相关的一条系绳涉及ER蛋白VAPB和线粒体蛋白PTPIP51之间的相互作用。最近的研究表明，在FTD/ALS中，ER-线粒体信号受到破坏，这涉及到VAPB-PTPIP51锚链的断裂。因此，纠正中断的系链可能会纠正FTD/ALS的许多其他下游受损特征。在这里，我们综述了这一主题的进展，特别强调将VAPB-PTPIP51锚链作为新的药物靶点。
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two major neurodegenerative diseases. FTD is the second most common cause of dementia and ALS is the most common form of motor neuron disease. These diseases are now known to be linked. There are no cures or effective treatments for FTD or ALS and so new targets for therapeutic intervention are required but this is hampered by the large number of physiological processes that are damaged in FTD/ALS. Many of these damaged functions are now known to be regulated by signaling between the endoplasmic reticulum (ER) and mitochondria. This signaling is mediated by “tethering” proteins that serve to recruit ER to mitochondria. One tether strongly associated with FTD/ALS involves an interaction between the ER protein VAPB and the mitochondrial protein PTPIP51. Recent studies have shown that ER-mitochondria signaling is damaged in FTD/ALS and that this involves breaking of the VAPB-PTPIP51 tethers. Correcting disrupted tethering may therefore correct many other downstream damaged features of FTD/ALS. Here, we review progress on this topic with particular emphasis on targeting of the VAPB-PTPIP51 tethers as a new drug target.