Does TDP-43 recruitment to stress granules (SGs) play a key role in ALS/FTD pathogenesis and does this present an opportunity for gene therapy?

Lead Research Organisation: King's College London
Department Name: Clinical Neuroscience

Abstract

Background: The aggregation of TDP-43 protein into insoluble cytoplasmic inclusions is the hallmark pathology in ~95% of ALS and 60% of FTD cases. TDP-43 is an RNA binding protein, which under oxidative and osmotic cellular stressors is recruited to SGs where they could form toxic oligomers. TDP-43 transgenic mice recapitulate pathological features of ALS/FTD in vivo and in organotypic spinal cord slice cultures.
Hypothesis: That suppression of SG formation will inhibit TDP-43 aggregation and reduce toxicity.
Primary aims:
1. Establish the temporal sequence of neurodegenerative changes in cortical and spinal cord slice cultures.
2. Define the temporal sequence of TDP-43 recruitment to SGs in spinal cord motor neurons in slice cultures.
3. Knock down key stress granule proteins using antisense and measure SG formation in slice cultures.
4. Knock down stress granule proteins using antisense and monitor TDP-43 recruitment and toxicity in cultures.
5. Knock down key stress granule proteins in transgenic mice using intraventricular injection of antisense and monitor the effects on cognitive and motor phenotype.

Publications

10 25 50
 
Description Teaching for The Brilliant Club 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact I took part in a weeklong teaching project for The Brilliant Club which engages 6th form students in classes and an essay taught and set by PhD students, who teach about their research area. I gave tutorials on ALS/FTD and the ethics of using animals in medical research.
Year(s) Of Engagement Activity 2019