Age-related diseases of the brain such as Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal dementia (FTD) and the motor neuron disease amyotrophic lateral sclerosis (ALS) have no cure or effective treatments. A common feature of these diseases is that certain proteins turn into solid masses in the brain of affected individuals. For example, in most people with ALS, and approximately half of the people with frontotemporal dementia, the RNA/DNA-binding protein TDP-43 becomes insoluble in affected brain cells. The cellular pathways that control TDP-43 and cause the protein to become insoluble in disease are unknown.

We are interested in how TDP-43 is controlled in health and disease. One focus in the lab is the role of poly(ADP-ribose) polymerases (PARPs) in controlling TDP-43 in ALS. PARPs are enzymes that link poly(ADP-ribose) on to target proteins. The poly(ADP-ribose) acts as a beacon for other proteins to lock on to and this serves to promote protein complex formation (see here for a description). To better understand this pathway and how it controls TDP-43 the lab uses a variety of approaches including genetics of the fruit fly, in vitro biochemical techniques, mammalian cell and neuronal culture systems and human neuropathology

We aim to work toward a broad understanding of how PARPs regulate TDP-43 in disease and to determine whether pharmacological strategies that target this pathway could have therapeutic potential in ALS and related neurological disorders.