Background:

Understanding the causes of dementia while people are alive can be difficult as many different proteins are linked to clinical problems. Symptoms offer clues but doctors rely on examining the brain after death find the exact culprit protein. In the brain diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), the culprit protein is TDP-43. Normally, TDP-43 is inside the cell’s control centre (nucleus) where it helps the cell build the instructions for making proteins. Here, TDP-43 helps select the useful  parts (exons) of the genetic template called RNA whilst removing the non-useful parts (introns) in a process called RNA splicing. In diseases like ALS and FTD, TDP-43 becomes trapped outside the nucleus in harmful clumps leading to mistakes in RNA splicing. When TDP-43 malfunctions, some intron parts are mistakenly defined as exons, leading to the presence of cryptic exons, which can have harmful consequences in brain cells. These cryptic exons only show up in disease tissue where TDP-43 protein isn’t working properly. Importantly, cryptic exons can be detected in the fluid around the spinal cord  before clinical symptoms arise. Additionally, TDP-43 is emerging as a potential culprit across ageing brain diseases. Yet, while cryptic exons are a very sensitive readout of TDP-43 problems, their expression across brain diseases has not yet been assessed.

Aims: How widespread is the TDP-43 problems and who's more at risk?

I will use computational biology skills to measure cryptic exon presence in  brains of people who have passed away with Alzheimer's, Parkinson’s, ALS, FTD, traumatic brain injuries, Huntington’s, Multiple sclerosis, as well as ageing brains and explore genetics between those who develop TDP-43 problems and those who don’t. This will give us a better understanding of what's going wrong and what prevents some people from developing TDP-43 problems as they age.