Investigating mechanisms of TDP-43 toxicity in Amyotrophic Lateral Sclerosis

Lead Research Organisation: University of Oxford
Department Name: Medical Sciences DTC


Transactive response DNA binding protein 43 kDa (TDP-43) is a ubiquitously expressed nuclear protein with important roles in regulating gene expression, through modulating splicing. TDP-43 has been identified as a major component of neuronal cytoplasmic inclusions in the majority (97%) of Amyotrophic Lateral Sclerosis (ALS) and almost half of frontotemporal dementia (FTD) patients. Furthermore, a number of mutations have been identified in the gene encoding TDP-43, TARDBP, which account for approximately 4% of familial ALS cases and a minority of sporadic cases, suggesting a direct role for TDP-43 in the pathogenesis of ALS. However, the mechanistic consequences of mutant TDP-43 remain unclear. Further work is required to pinpoint key pathways through which TDP-43 may act to initiate neurodegeneration and subsequent motor neuron loss.

This project aims to investigate mechanisms of TDP-43 toxicity in embryonic stem cell derived motor neurons (ESC-MNs) carrying the disease-associated mutation M337V. The effects of the M337V mutation on cellular phenotypes including TDP-43 mislocalisation, stress granule formation, axonal transport, cellular mitochondrial respiration and glycolysis will be investigated. The interaction of TDP-43 with proteins related to stress granule dynamics and nucleocytoplasmic transport will also be investigated. This study will shed light on the mechanisms of mutant TDP-43 toxicity in ALS and may highlight novel targets for therapeutic intervention.


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Description Poster Presentation (ALS International Symposium) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Poster presentation given at the ALS International Symposium. Allowed me to discuss my work and methodology with other postgraduate students.
Year(s) Of Engagement Activity 2019