Title: Road to neurodegeneration: characterisation of a novel TDP-43 mutation in motor neurone disease pathogenesis
Funder: The Academy of Medical Sciences

Abstract: Affecting millions of people world-wide, the impact of neurodegenerative diseases is expected to grow as our ageing population expands. With no effective treatment, we are in urgent need for better understanding of disease-causing mechanisms. Most of the neurodegenerative diseases are characterised by the accumulation of aberrant protein aggregates in affected brain areas, one of which is TDP-43, found in patients with Motor Neurone Disease (MND) and Frontotemporal Dementia (FTD). The aim of this project is to gain insight into the mechanisms involved in TDP-43 aggregation and to characterise the impact of the protein on cells’ global transcriptome, response to stress and survival. Having recently reported a novel MND/FTD-causing mutation, we are the first to link the loss of RNA-binding of TDP-43 to the disease. To further characterise how the mutant protein exerts its toxicity on different cells, we will utilise cell type-specific promoters to drive neuronal- or astrocyte-specific expression of TDP-43 in primary rat cells to see whether TDP-43 causes different responses in neurones and astrocytes. We will monitor the movement and cytotoxicity of the protein in cells under normal or stress conditions. We will also investigate the potential non-cell autonomous effects, examining the communication between neurones and astrocytes during the build-up of TDP-43 aggregation and toxicity. Finally, the global transcriptome profile of neuronal cells expressing mutant TDP-43 will be examined to shed lights on the downstream pathogenesis mechanisms that lead to neurodegeneration.

Lay abstract: Neurodegenerative diseases are age-related progressive disorders caused by the death of neurones in different brain areas. The cause of neuronal death is still unclear, but most neurodegenerative diseases show abnormal toxic protein aggregates in the brain area where neurones die. In order to understand and cure neurodegenerative diseases, it is vital that we gain a better understanding of why and how these abnormal proteins aggregate. This project focuses on one such protein, called TDP-43, which aggregates in the brain of patients with Motor Neurone Disease and Frontotemporal Dementia. Prior to this project, we have identified a novel mutation in this protein that causes it to lose the ability to interact with RNA and leads to TDP-43 aggregates in cells. TDP-43 is an RNA-binding protein involved in regulating thousands of other genes’ expression in brain cells. However, the roles of the RNA interaction of TDP-43 in disease development have not been well characterised before. This project will establish how the expression of this mutant TDP-43 impairs the normal function, the response to environmental stimulation and the health and survival of neurones. We will also examine the role of neuronal supporting cells, astrocytes, in facilitating the function of neurones expressing the mutant TDP-43. In addition, the gene expression profile affected by mutant TDP-43 will be examined. The results will determine the manner and the consequence of TDP-43 aggregation, allowing us to evaluate the potential of therapeutic intervention.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL