Dr Leeanne McGurk
We aim to understand the causative mechanisms of the motor neuron disease amyotrophic lateral sclerosis (ALS) by elucidating how TDP-43, a protein that controls RNA biogenesis and causes ALS, functions in health and disease. ALS results in paralysis and death within 2-5 years of symptomatic onset and currently there is no cure or effective treatments. Understanding how TDP-43 controls RNA biogenesis e.g., RNA processing, RNA stability, RNA localization etc. may lead to future therapeutic options.
We aim to identify TDP-43-controlled mechanisms that cause neuronal death so that we can identify pathways and RNAs misregulated in ALS.
We aim to elucidate how RNAs are controlled by TDP-43 so we can begin to understand the molecular mechanisms underpinning ALS.
We aim to elucidate how TDP-43 controlled RNAs regulate neurons so we can determine if pathways downstream of TDP-43 are potential biomarkers or therapeutic targets.
To do this we use state-of-the-art sequencing technologies, biochemical approaches, and mass spectrometry to understand the disease process in Drosophila with ALS symptoms similar to humans, in human neuronal cells and in human brain tissue. We combine Drosophila genetics with human brain tissue to identify TDP-43-controlled mechanisms that cause neuronal death. We use state-of-the-art sequencing technologies and biochemical assays to elucidate how RNAs are controlled by TDP-43. We use mass spectrometry in Drosophila and human neuronal cells to elucidate how TDP-43-controlled RNAs regulate neurons.
We aim to work toward a broad understanding of how motor neurons degenerate in ALS as this may lead to novel pharmacological strategies that could have therapeutic potential.
(For full list of publication see google scholar: https://scholar.google.co.uk/citations?hl=en&user=ld22yZgAAAAJ&view_op=list_works&sortby=pubdate)
Selected Research Articles
François-Moutal L, Scott D, Ambrose A, Zerio C, Dissanayake K, May D, Carlson J, Barbieri E, Moutal A, Roux K, Shorter J, Khanna R, Barmada S, McGurk L, Khanna M. Heat Shock Protein Grp78/BiP/HspA5 Binds Directly to TDP-43 and Mitigates Toxicity Associated with Neurodegenerative Disease Pathology. 2021 preprint. Research square DOI: 10.21203/rs.3.rs-1090289/v1
McGurk L, Rifai OR, Shcherbakova O, Byrns CN, Carranza F, Zhou HW, Kim HJ, Zhu Y, Bonini NM. Toxicity of pathogenic ataxin-2 in Drosophila shows dependence on a pure CAG repeat sequence. Human Molecular Genetics, 2021. online here
#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 . # denotes corresponding authors.
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
Hayashi Y, Ford, LK, Fioriti L, McGurk L, Zhang M. Liquid-liquid phase separation in physiology and pathophysiology of the nervous system. Journal of Neuroscience, 2021, 41 (5) 834-844. online here
#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