Killam Seminar Series: Tackling sporadic ALS-FTD through TDP-43 knockin models

The Killam Seminar Series presents Tackling sporadic ALS-FTD through TDP-43 knockin models.

The seminar will be taking placed in person at The Neuro (Jeanne Timmins Ampitheatre)

To attend in person, register here

To attend virtually, register here.

Speaker: Jemeen Sreedharan, MD, PhD

Neurologist, King's College London, UK

Abstract: ALS is a largely sporadic motor neuron disease without cure. 97% of cases demonstrate cytoplasmic aggregation and nuclear depletion of the RNA binding protein TDP-43. Mutations in TARDBP, the gene encoding TDP-43, account for only ~1% of all ALS cases but offer an opportunity to understand the mechanisms underlying disease. Most TDP-43 studies have focussed on transgenic overexpression of TDP-43 to recapitulate histopathological hallmarks of disease, but these models may demonstrate artefacts of transgenesis. We have used CRISPR to generate disease models more reflective of the human condition at the genetic level. We have discovered that Tardbp mutation can disturb TDP-43 autoregulation in mice, causing cognitive rather than motor phenotypes. TARDBP mutation can also disturb autoregulation in human cells. We have been working to develop the TDP-43(Q331K) knock-in mouse as a translational tool using in vivo 9.4T MRI to guide molecular studies. Our iPSC tools are currently being used to better understand the mechanisms of TDP-43 autoregulation and to develop platforms for genetic and small-molecule regulators of TDP-43 expression. We are only scratching the surface in these preliminary studies and a more extensive characterisation of TARDBP mutations using knock-in approaches may be of great value.

Bio: I am a neurologist with a research interest in TDP-43, a DNA/RNA-binding protein that is dysregulated in motor neuron disease and dementia including frontotemporal dementia and Alzheimer's disease. TDP-43 levels in the brain are exquisitely regulated in health by autoregulation, but this mechanism is disturbed in disease. My laboratory has developed human cellular and mouse model systems to understand autoregulation with a view to normalising TDP-43 expression for therapeutic gain. We use genetic engineering technologies to create more realistic models of disease than ever before. We also aim to understand the structural, functional and molecular effects of TDP-43 misregulation on brain development, as age-related neurodegenerative diseases probably start much earlier in life than previously thought. In 2019 I received the Alzheimer’s Research UK David Hague Early Career Investigator Award. My other roles include being module 3 lead for the MSc in Clinical Neuroscience and teaching medical students clinical neurology.

Supported by the generosity of the Killam Trusts , The Neuro’s Killam Seminar series hosts outstanding guest speakers.