Investigating mechanisms of TDP-43 toxicity in Amyotrophic Lateral Sclerosis

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.