TDP-43 Autoregulation
Amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) is a devastating disease spectrum characterised by pathology of the 43-kDa TAR DNA-binding protein (TDP-43). Understanding how TDP-43 contributes to neurodegeneration will help direct therapeutic efforts. In ALS-FTD TDP-43 autoregulation is disrupted, resulting in increased TDP-43 function and altered splicing of other genes involved in dementia. My lab is interested in deciphering the mechanisms of perturbation to autoregulation in TDP-43 and its impact in neuronal function. We are using in-vivo models as well as human stem-cell derived neurones. This allows us to retain the endogenous gene structure, including promoters and autoregulatory 3′ UTR and maintain the ubiquitous expression of TDP-43 during embryonic development and in adulthood.
Axonal Degeneration
Axon degeneration is one of the characteristics of ALS. One form of axon degeneration occurs when the axon is damaged and the axon distal to the injury starts to fragment in a process called Wallerian degeneration. One of the most down-stream molecules in Wallerian degeneration is the pro-degenerative molecule, SARM1. We believe that SARM1 could be a therapeutic target to alleviate axon degeneration in ALS. My lab is using CRISPR editing, electrophysiology and imaging to generate and characterise human stem-cell derived motor neurons with SARM1 mutations that have been linked to ALS, in the hopes of generating a model to test ALS therapies.
The impact of TDP-43 on microglial biology
Converging lines of evidence from human genetics, neuroimaging and post-mortem brain tissue studies suggest that microglia are major contributors to molecular and phenotypic changes in neurodegenerative conditions such as ALS and FTD. Microglia constantly survey the brain parenchyma for debris, apoptotic cells, aberrant misfolded proteins, and pathogens. Critically, microglial activation in response to detrimental stimuli is tightly controlled. My lab is interested in the role of TDP-43 in regulating microglial phenotypic changes, including inflammatory response and synaptic engulfment and how these changes lead to ALS and FTD related pathological changes. Using hiPSC derived microglia models and a combination of high throughput imaging, genetic and biochemical manipulations we are working to decipher the brain's biological defences.
