Studying the role of TDP-43 induced damage to the VAPB-PTPIP51 ER-mitochondria tethers in fronto-temporal dementia/amyotrophic lateral sclerosis

阿尔茨海默病和相关痴呆症、帕金森病和运动神经元病是主要的神经退行性疾病，困扰着我们大部分人口，给我们的医疗保健系统和经济带来巨大负担。这些疾病都无法治愈，对于痴呆和运动神经元疾病，甚至没有减缓疾病进展的有效方法。因此，迫切需要确定治疗这些疾病的新治疗靶点。在所有这些神经退行性疾病中，许多细胞过程都受到干扰。这些包括神经细胞中钙浓度的损害、脂肪代谢、线粒体（细胞的能量产生者）、神经细胞内蛋白质和线粒体的运输、细胞应激反应的激活以及自噬过程的改变，该过程从细胞中去除受损的蛋白质。最后，所有这些疾病中都存在炎症。难题在于，所有这些明显不同的细胞过程的损伤是如何在神经退行性疾病中共同发生的。此外，这些受损特征的多样性使得设计新的治疗策略变得困难。哪些受损的细胞功能应优先作为治疗靶点？最近的几项研究重点关注细胞的两个组成部分，内质网（ER）和线粒体，在神经退行性疾病中如何相互沟通。这是因为内质网-线粒体通讯会影响上述在这些疾病中受损的大多数细胞过程。我们和其他人已经证明，内质网-线粒体通讯在痴呆、帕金森病和运动神经元疾病中受到干扰。重要的是，我们已经确定了 ER 和线粒体沟通的机制。它涉及 ER 蛋白 VAPB 与线粒体蛋白 PTPIP51 的结合；这种结合作用是束缚两个细胞成分，从而促进通讯。我们继续证明 VAPB-PTPIP51 系链在一些神经退行性疾病中受损。该项目重点关注额颞叶痴呆 (FTD) 和肌萎缩侧索硬化症 (ALS)。 FTD 是继阿尔茨海默氏病之后老年性痴呆的第二大常见原因，而 ALS 是运动神经元疾病的最常见原因。 FTD 和 ALS 在临床上与许多患有这两种疾病的患者有关。 TDP-43 是一种与 FTD/ALS 密切相关的蛋白质；大多数 FTD/ALS 患者受影响的神经元中都可见异常 TDP-43 沉积，TDP-43 基因突变是某些遗传性疾病的原因。 TDP-43 还与阿尔茨海默病和帕金森病有关。值得注意的是，我们已经证明 TDP-43 会破坏 VAPB-PTPIP51 系链和 ER-线粒体信号传导。该项目的目的是确定 ER-线粒体信号传导和 VAPB-PTPIP51 系链的损伤是否代表导致 TDP-43 相关 FTD/ALS 疾病的致病事件。目标是： 1. 确定一些 FTD/ALS 动物模型中 ER 线粒体信号传导破坏的时间序列。这将揭示ER-线粒体信号传导的损伤是否代表疾病的早期特征。2．确定携带致病性 TDP-43 突变的人类患者衍生神经元中 ER 线粒体信号传导是否受到破坏。这将为动物模型的研究结果提供临床相关性。3．确定通过过表达 VAPB 或 PTPIP51 来纠正 TDP-43 诱导的 ER-线粒体接触松动是否在细胞模型中具有保护作用。如果我们发现 TDP-43 诱导的 VAPB-PTPIP51 系链损伤是一种早期疾病特征，也发生在患者神经元中，并且纠正这种损伤具有保护性，那么将为开发修复疾病中受损的 ER-线粒体信号传导的药物提供强有力的支持。

Alzheimer's disease and related dementias, Parkinson's disease and motor neuron disease are major neurodegenerative diseases that afflict large proportions of our population and exert huge burdens on our healthcare system and economy. There are no cures for any of these diseases and for dementia and motor neuron disease there are not even effective ways of slowing disease progression. There is thus an urgent need to identify new therapeutic targets for treating these diseases.A number of cellular processes are perturbed in all of these neurodegenerative diseases. These include damage to calcium concentrations in nerve cells, fat metabolism, mitochondria (the energy producers of the cell), transport of proteins and mitochondria within nerve cells, activation of cellular stress responses and alterations to a process termed autophagy which removes damaged proteins from cells. Finally, inflammation is seen in all of these diseases. The conundrum is how damage to all these apparently disparate cellular processes occurs collectively in neurodegenerative diseases. Moreover, the diversity of these damaged features makes devising new treatment strategies difficult; which damaged cellular function should be prioritized as a therapeutic target?Several recent studies have focused attention on how two components of the cell, the endoplasmic reticulum (ER) and mitochondria, communicate with each other in neurodegenerative diseases. This is because ER-mitochondria communications impact upon most of the cellular processes described above that are damaged in these diseases. We and others have shown that ER-mitochondria communications are perturbed in dementia, Parkinson's disease and motor neuron disease. Importantly, we have identified a mechanism by which ER and mitochondria communicate. It involves binding of the ER protein VAPB to the mitochondrial protein PTPIP51; this binding acts to tether the two cellular components so as to facilitate communication. We have gone on to show that the VAPB-PTPIP51 tethers are damaged in some neurodegenerative diseases.This project focuses on fronto-temporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). FTD is the second most common cause of presenile dementia after Alzheimer's disease and ALS is the most common cause of motor neuron disease. FTD and ALS are clinically linked with many patients displaying aspects of both diseases. TDP-43 is a protein that is strongly associated with FTD/ALS; abnormal TDP-43 deposits are seen in affected neurons in most FTD/ALS patients and mutations in the TDP-43 gene are the cause of some inherited forms of the disease. TDP-43 is also linked to Alzheimer's and Parkinson's diseases. Notably, we have shown that TDP-43 disrupts the VAPB-PTPIP51 tethers and ER-mitochondria signaling. The aim of this project is to determine whether damage to ER-mitochondria signaling and the VAPB-PTPIP51 tethers represent pathogenic events that contribute to disease in TDP-43 linked FTD/ALS. The Objectives are: 1. To determine the temporal sequence of ER-mitochondria signaling disruption in some animal models of FTD/ALS. This will reveal whether damage to ER-mitochondria signaling represents an early feature of disease.2. To determine whether ER-mitochondria signaling is disrupted in human patient derived neurons carrying pathogenic TDP-43 mutations. This will provide clinical relevance to the findings in the animal models.3. To determine whether correcting TDP-43 induced loosening of ER-mitochondria contacts via overexpression of VAPB or PTPIP51 is protective in cell models.If we find that TDP-43 induced damage to the VAPB-PTPIP51 tethers is an early disease feature which also occurs in the patient neurons, and that correcting this damage is protective, it will lend strong support for developing drugs which remedy damaged ER-mitochondria signaling in disease.