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 mislocalised 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.
*McGurk L, Rifai O and *Bonini NM. (2019) Poly(ADP-ribosylation) in age-related neurological disease. Trends in Genetics 35 (8) p601-613. * denotes corresponding authors. doi/10.1016/j.tig.2019.05.004 PMCID 6625889 PMID 31182245. Read Article
McGurk L1, Gomes E1, Guo L1, Shorter J, and Bonini NM.(2018) The N-terminal domain regulates TDP-43 aggregation. Biochemistry. 2018, 57 (51), 6923-6926.
McGurk L, Mojsilovic-Petrovic J, Van Deerlin V, Shorter J, Kalb RG, Lee VM, Trojanowksi JQ, Lee EB and Bonini NM (2018) Nuclear Poly(ADP-ribose) Activity is a Therapeutic Target in Amyotrophic Lateral Sclerosis. Acta Neuropathologica Communications. 2018, 6: 84. doi/10.1186/s40478-018-0586-1 PMCID 6114235 PMID 30157956. Read Article
McGurk L, Gomes E, Guo E, Mojsilovic-Petrovic J, Tran V, Kalb RG, Shorter J, Bonini NM (2018) Poly(ADP-ribose) prevents aberrant phase separation of TDP-43 by promoting liquid demixing and stress granule localization. Molecular cell. 2018, 71, 703-707. doi/10.1016/j.molcel.2018.07.002 PMCID 6128762 PMID:30100264. Read Article
McGurk L, Berson A, Bonini NM. Drosophila as an In Vivo Model for Human Neurodegenerative Disease. Genetics (2015). Genetics 2015 Oct; 201(2):377-402. PMCID 4596656 PMID: 26447127. Read Article
McGurk L, Lee VM, Trojanowksi JQ, Van Deerlin VM, Lee EB, Bonini NM (2014) Poly-A Binding Protein- 1 Localization to a Subset of TDP-43 Inclusions in Amyotrophic Lateral sclerosis occurs more frequently in patients harboring an expansion in C9orf72. J Neuropathol Exp Neurol. 2014, Sep;73(9):837-45. doi/10.1097/NEN.0000000000000102 PMCID 4149258 PMID 25111021. Read Article
Kim HJ, Raphael AR, Ladow ES, McGurk L, Weber RA, Trojanowski JQ, Lee VM, Finkbeiner S, Gitler AD, Bonini NM. Therapeutic modulation of eIF2α phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models. Nat Genet. 2014, Feb;46(2):152-60. doi/10.1038/ng.2853 PMCID 3934366 PMID 24336168. Read Article