Protein aggregation is central to dementia and motor neuron disease. Understanding how proteins become aggregated in disease will help us to better understand potential causes and may lead to new treatments. A key example protein is TDP-43, which causes disease when it leaves the nucleus to form cytoplasmic aggregates in affected brain regions of several dementias, including 45% of frontotemporal dementia (FTD), ~57% of Alzheimer’s disease and >95% of amyotrophic lateral sclerosis (ALS). The McGurk lab has a long-standing interest in defining mechanisms that underlie TDP-43-induced disease. We have discovered that enzymes that generate polyADP-ribose – which are negatively charged polymers that resemble RNA- are important for propagating TDP-43 accumulation in the cytoplasm and disease toxicity. We aim to define how the polyADP-ribose polymerases function in neurons so that we better understand how disease happens and potentially reveal new avenues of therapeutic research. To do this, our lab uses Drosophila genetics, biochemical assays, neuronal cell culture systems and human neuropathology as this enables us to watch disease happen over the lifetime of the animal, understand molecular function, and translate our findings to people diagnosed with dementia and motor neuron disease.
The student that joins our research team will develop their own research project on the poly(ADP-ribose) polymerases in this area, giving them the expertise needed for a future career in research.