Senior Postdoctoral Scientist
Developing a high throughput screening pipeline to identify drugs promoting survival in M337V TDP-43 motor neurons
My research is focussed on using mouse models to study the mechanisms underlying the loss of motor neurons that characterises amyotrophic lateral sclerosis (ALS). My ultimate aim is to identify new pathways driving ALS, or drugs that can improve translational outcomes for people living with the disease. I am particularly interested in the role of a protein called TDP-43, in which the presence of mutations drive onset and progression of ALS, as well as the adverse effects of oxidative stress on motor neuron loss.
Most recently we have utilised a cell culture model in which an ALS-associated mutant human TDP-43 is expressed in mouse embryonic stem cells, which can then be programmed to become motor neurons in vitro. Using these cells as a drug-discovery platform in high throughput screens, we have identified, and are currently validating, candidate drugs in our mouse and human cell culture models.
Neuronal over-expression of Oxr1 is protective against ALS-associated mutant TDP-43 mislocalisation in motor neurons and neuromuscular defects in vivo.
Williamson MG. et al, (2019), Hum Mol Genet, 28, 3584 - 3599
The interactome of human TDP-43 in a cellular model of amyotrophic lateral sclerosis
Feneberg E. et al, (2019), EUROPEAN JOURNAL OF NEUROLOGY, 26, 221 - 222
Single-copy expression of an amyotrophic lateral sclerosis-linked TDP-43 mutation (M337V) in BAC transgenic mice leads to altered stress granule dynamics and progressive motor dysfunction.
Gordon D. et al, (2019), Neurobiol Dis, 121, 148 - 162
Absence of wide-spread mis-splicing in the preclinical phase of a native promoter driven TDP-43 mouse model of ALS
Scaber J. et al, (2016), EUROPEAN JOURNAL OF NEUROLOGY, 23, 797 - 797
TDP-43 is cytoplasmically mislocalized and associated with impaired stress responses and survival of primary neurons from symptomatic amyotrophic lateral sclerosis (ALS) mice
Farrimond L. et al, (2016), EUROPEAN JOURNAL OF NEUROLOGY, 23, 390 - 391
TARDBP pathogenic mutations increase cytoplasmic translocation of TDP-43 and cause reduction of endoplasmic reticulum Ca²⁺ signaling in motor neurons.
Mutihac R. et al, (2015), Neurobiol Dis, 75, 64 - 77