Motor neurone disease (MND) and frontotemporal dementia (FTD) are both fatal neurodegenerative diseases that currently lack effective treatments. Many people living with these diseases develop pathology within neurons that is characterised by alterations to an essential protein known as TDP-43. This protein is normally found in the nucleus, but in disease TDP-43 aggregates, accumulates in the cytoplasm of neurons, and is extensively modified by post-translation modifications. However, how TDP-43 malfunction leads to either MND or FTD or both diseases together, remains unclear. By uncovering the molecular mechanisms involved in TDP-43 aggregation and toxicity, Dr Adam Walker’s laboratory aims to identify new potential therapeutic targets for these devastating diseases. 

The Walker lab uses biochemistry and imaging techniques to study neuronal cell culture and genetically modified mouse models of MND and FTD, alongside analysis of human brain and spinal cord samples, to investigate the involvement of TDP-43 in disease. Importantly, Dr Walker previously characterised new TDP-43 mice that develop both pathology and motor phenotypes reminiscent of human disease, which are a vital new tool for both investigations of disease mechanisms and pre-clinical testing of therapeutics. Excitingly, Dr Walker showed that removal of TDP-43 pathology can allow mice to recover from disease even after degeneration of neurons and muscles has occurred, providing hope that future compounds that can achieve TDP-43 clearance in humans will be effective even after symptom onset.

On-going studies in the lab aim to identify the key protein components of TDP-43 pathology and the causes of TDP-43 malfunction, and to determine the role of cellular stress responses and glial alterations in disease pathogenesis. We are also using advanced quantitative proteomics studies to develop global maps of the biochemical changes caused by alterations in TDP-43, and to reveal previously unrecognised mechanisms of disease. We are now also conducting pre-clinical studies in collaboration with other laboratories in Australia and the USA, to test potential drug candidates for MND and FTD.

Group leader

Dr Adam Walker

Dr Adam Walker

Ross Maclean Fellow, Queensland Brain Institute

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