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

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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.