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的痴呆症、帕金森氏病和运动神经元疾病是主要的神经退行性疾病，困扰着我们很大一部分人口，并给我们的医疗体系和经济带来巨大的负担。这些疾病中的任何一种都没有治愈的方法，对于痴呆症和运动神经元病，甚至没有有效的方法来减缓疾病的进展。因此，迫切需要确定治疗这些疾病的新的治疗靶点。在所有这些神经退行性疾病中，许多细胞过程都受到干扰。这些包括损害神经细胞中的钙浓度、脂肪代谢、线粒体(细胞的能量产生者)、蛋白质和线粒体在神经细胞内的运输、细胞应激反应的激活以及被称为自噬的过程的改变，该过程将受损的蛋白质从细胞中移除。最后，在所有这些疾病中都可以看到炎症。难题是，在神经退行性疾病中，所有这些明显不同的细胞过程是如何共同受到损害的。此外，这些受损特征的多样性使设计新的治疗策略变得困难；哪种受损的细胞功能应该优先作为治疗靶点？最近的几项研究将注意力集中在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-线粒体通讯影响到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-线粒体通讯在痴呆症、帕金森病和运动神经元病中受到干扰。重要的是，我们已经确定了一种内质网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；这种结合作用将两个细胞成分捆绑在一起，从而促进通信。我们继续展示了VAPB-PTPIP51在一些神经退行性疾病中被破坏。这个项目专注于额颞叶痴呆(FTD)和肌萎缩侧索硬化症(ALS)。FTD是仅次于阿尔茨海默病的第二大最常见的老年性痴呆症原因，ALS是运动神经元病的最常见原因。FTD和ALS在临床上与许多患者表现出这两种疾病的各个方面有关。TDP-43是一种与FTD/ALS密切相关的蛋白质；在大多数FTD/ALS患者的受累神经元中可以看到TDP-43的异常沉积，TDP-43基因的突变是一些遗传性疾病的原因。TDP-43还与阿尔茨海默氏症和帕金森氏症有关。值得注意的是，我们已经表明TDP-43破坏了VAPB-PTPIP51系链和ER-线粒体信号。该项目的目的是确定ER-线粒体信号和VAPB-PTPIP51锚链的损伤是否代表TDP-43连锁的FTD/ALS疾病的致病事件。本研究的目的是：1.确定FTD/ALS动物模型中ER-线粒体信号中断的时间序列。这将揭示内质网线粒体信号的损伤是否代表疾病的早期特征。为了确定携带致病TDP-43突变的人类患者来源的神经元中的ER-线粒体信号是否中断。这将为动物模型中的研究结果提供临床意义。为了确定纠正TDP-43通过过度表达VAPB或PTPIP51而导致的ER-线粒体接触松动在细胞模型中是否具有保护性。如果我们发现TDP-43诱导的VAPB-PTPIP51连接的损伤是一种早期疾病特征，并且纠正这种损伤是保护性的，这将为开发治疗疾病中受损的ER-线粒体信号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.