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., & Bonini, N. M. (2020). TDP-43, a protein central to amyotrophic lateral sclerosis, is destabilized by tankyrase-1 and -2. Journal of Cell Science, 133(12). https://doi.org/10.1242/jcs.245811
Deng P., Khan A., Jacobson D., Sambrani N., McGurk L., Jayasree A., Hejatko J., Shohat-Ophir G., O’Connell M.A., Li JB and Keegan L.P (2020) Adar RNA editing-dependent and -independent effects are required for brain and innate immune functions in Drosophila. Nature Communications 2020, vol 11, Article 1580. doi/10.1038/s41467-020-15435-1 PMCID 7101428 PMID 32221286. Read Article
Khan A., Paro S., McGurk L., Sambrani N, Hogg M., Brindle J., Pennetta G., Keegan L.P., O'Connell M.A (2020) Membrane and synaptic defects leading to neurodegeneration in Adar mutant Drosophila are rescued by increased autophagy. BMC Biol 2020, 18 (1), 15. Underlined contributed equally. doi/10.1186/s12915-020-0747-0 PMCID 7020516 PMID 32059717. Read Article
*McGurk L., Rifai O and *Bonini N.M (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 L., Gomes E., Guo L., Shorter J and Bonini N.M (2018) The N-terminal domain regulates TDP-43 aggregation. Biochemistry. 2018, 57 (51), 6923-6926. Read Article
McGurk L., Mojsilovic-Petrovic J., Van Deerlin V., Shorter J., Kalb RG., Lee V.M., Trojanowksi J.Q., Lee E.B and Bonini N.M (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 R.G., Shorter J., Bonini N.M (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 N.M (2015) Drosophila as an In Vivo Model for Human Neurodegenerative Disease. Genetics 2015 Oct; 201(2):377-402. PMCID 4596656 PMID: 26447127. Read Article
McGurk L., Lee V.M., Trojanowksi J.Q., Van Deerlin V.M., Lee E.B., Bonini N.M (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 H.J., Raphael A.R., Ladow E.S, McGurk L., Weber R.A, Trojanowski J.Q, Lee V.M., Finkbeiner S., Gitler A.D., Bonini N.M (2014) 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
McGurk L and Bonini N.M (2012) Protein interacting with C kinase (PICK1) is a suppressor of spinocerebellar ataxia 3-associated neurodegeneration in Drosophila. Hum Mol Genet. 2012, Jan 1;21(1):76-84. doi/10.1093/hmg/ddr439 PMCID 3235011 PMID: 21949352. Read Article
McGurk L and Bonini N.M (2011) Yeast informs Alzheimer's disease. Science. 2011, Dec 2;334(6060):1212-3. doi/10.1126/science.1216073 PMID: 22144604. Read Article
Keegan L.P., McGurk L., Palavicini J.P., Brindle J., Paro S., Li X., Rosenthal J.J., O'Connell M.A (2011) Functional conservation in human and Drosophila of Metazoan ADAR2 involved in RNA editing: loss of ADAR1 in insects. Nucleic Acids Res. 2011, Sep 1;39(16):7249-62. doi/10.1093/nar/gkr423 PMCID 3167634 PMID: 21622951. Read Article
Heale B.S., Keegan L.P., McGurk L., Michlewski G., Brindle J., Stanton C.M., Caceres J.F., O'Connell M.A (2009) Editing independent effects of ADARs on the miRNA/siRNA pathways. EMBO J. 2009, 21; 28(20):3145-56. doi/10.1038/emboj.2009.244 PMCID 2735678 PMID: 19713932. Read Article
McGurk L., Pathirana S., Rothwell K., Trimbuch T., Colombini P., Yu F., Chia W., Bownes M (2008) The RGS gene loco is essential for male reproductive system differentiation in Drosophila melanogaster. BMC Dev Biol. 2008, Apr 3; 8:37. doi/10.1186/1471-213X-8-37 PMCID 2324087 PMID 18387173. Read Article
McGurk L., Morrison H., Keegan L.P., Sharpe J., O'Connell M.A (2007) Three-dimensional imaging of Drosophila melanogaster. PLoS One. 2007, Sep 5;2(9): e834. doi/10.1371/journal.pone.0000834 PMCID 1952176 PMID: 17786206. Read Article
McGurk L., Tzolovsky G., Spears N., Bownes M (2006) The temporal and spatial expression pattern of myosin Va, Vb and VI in the mouse ovary. Gene Expr Patterns. 2006, doi/10.1016/j.modgep.2006.03.002 PMID: 16713372. Read Article
AS Raikhel AS., McGurk L., Bownes M. Ecdysteroid action in insect reproduction. Encyclopedia of hormones. Academic Press, San Diego, Calif, 2003,451-459.