Dr Leeanne McGurk

Poly(ADP-ribosylation), also known as PARylation, is a highly dynamic and reversible post-translational modification where chains of ADP-ribose are linked to target proteins by PAR-polymerases and removed by ADP-ribose hydrolases. PARylation is central to signalling pathways such as the stress response, has been implicated as either causative or activated in neurodevelopmental and neurodegenerative disorders, and, regulates a set of proteins pivotal to age-related brain disease.

Our research focuses on understanding the role that PARylation plays in either promoting or preventing aging of the brain. An emerging model is that PARylation is important for regulating the localization and solubility of proteins known to cause neurodegenerative disease. One such protein is TDP-43, an RNA-binding protein mislocalized to the cytoplasm as insoluble clumps of protein in several neurodegenerative disorders including amyotrophic lateral sclerosis (ALS). Our research indicates that TDP-43 binds to PAR and this function localizes the protein to cytoplasmic structures called stress granules, where upon persistent localisation TDP-43 transitions into disease-like aggregates.

Currently, we are focused on the PAR-polymerases and understanding the role they play in regulating TDP-43. To do this, the lab uses a variety of approaches including genetics of the fruit fly, in vitro biochemical techniques with mammalian cell and neuronal culture systems. We aim to work toward a broad understanding of how PARylation is involved in brain function and to determine whether pharmacological strategies that target this pathway could have therapeutic potential in neurological disease.

Selected Publications

For full list of publications see Google Scholar.

Research Articles

• Heat Shock Protein Grp78/BiP/HspA5 Binds Directly to TDP-43 and Mitigates Toxicity Associated with Neurodegenerative Disease. François-Moutal et al. (2022)
• Toxicity of pathogenic ataxin-2 in Drosophila shows dependence on a pure CAG repeat sequence. McGurk et al. (2021)
• TDP-43, a protein central to amyotrophic lateral sclerosis, is destabilized by tankyrase-1 and -2. McGurk et al. (2020) - co-corresponding author
• Nuclear Poly(ADP-ribose) Activity is a Therapeutic Target in Amyotrophic Lateral Sclerosis. McGurk et al. (2018)
• Poly(ADP-ribose) prevents aberrant phase separation of TDP-43 by promoting liquid demixing and stress granule localization. McGurk et al. (2018)

Reviews

• Liquid-liquid phase separation in physiology and pathophysiology of the nervous system. Hayashi et al. (2021)
• Poly(ADP-ribosylation) in age-related neurological disease. McGurk et al. (2019) - co-corresponding author