Our Research Group maps new signalling pathways regulating neuroplasticity in the brain, particularly synaptic transmission, neurite outgrowth/synapse formation and neurogenesis. Of particular interest is a kinase called GSK3, which has been shown to be an important regulator of synaptic transmission and neurogenesis. Its activity is elevated in Bipolar disorder and Schizophrenia. Accordingly, GSK3 is an established target of lithium and other mood stabilizers used to treat Bipolar patients.
GSK3 inhibitors are also in clinical trials for stroke/brain injury rehabilitation, age-related cognitive decline and Alzheimer’s Disease. We believe it is important to identify the pathologic targets of GSK3 in mood disorders and neurodegenerative conditions, since these could become new therapeutic targets that are more potent and specific (fewer side effects) than current GSK3 inhibitors. So far, we have discovered many novel substrates, including trafficking proteins, signalling proteins and transcription factors. We investigate their physiological function and roles in neurological disease using Drosophila as a model organism. Our ability to map novel signalling pathways and to characterise their function in vivo puts us in a strong position to make clinically important breakthroughs for improved treatment of mental disorders.
Cole AR. GSK3 substrates in mood disorders and schizophrenia. FEBS Journal 2013; 280(21):5213-27.
Cole AR. GSK3 as a sensor determining cell fate in the brain. Frontiers in Molecular Neuroscience 2012; 5:4.
Williamson R, van Aalten L, Mann DMA, Platt B, Plattner F, Bedford L, Mayer J, Howlett D, Usardi A, Sutherland C and Cole AR. CRMP2 hyperphosphorylation is characteristic of Alzheimer’s disease and not a feature common to other neurodegenerative diseases. Journal of Alzheimer’s Disease. 2011; 27(3):615-25.
Farghaian H, Turnley AM, Sutherland C and Cole AR. Bioinformatic prediction and confirmation of β-adducin as a novel substrate of glycogen synthase kinase 3. J. Biol. Chem. 2011; 286:25274-83.
Astle MV, Ooms LM, Cole AR, Binge LC, Dyson JM, Layton MJ, Petratos S, Sutherland C and Mitchell CA. Identification of a proline-rich inositol polyphosphate 5-phosphatase (PIPP): collapsin response mediator protein 2 (CRMP2) complex that regulates neurite elongation. J. Biol. Chem. 2011; 286:23407-18.
Farghaian H, Yu C, Fu AW, Fu AK, Ip JP, Ip NY, Turnley AM and Cole AR. Scapinin-induced inhibition of axon elongation is attenuated by phosphorylation and translocation to the cytoplasm. J. Biol. Chem. 2011; 286:19724-34.
Clayton EL, Sue N, Smillie KJ, O’Leary T, Bache N, Cheung G, Cole AR, Wyllie DJ, Sutherland C, Robinson PJ and Cousin MA. DynaminI phosphorylation by GSK3 controls activity-dependent bulk endocytosis of synaptic vesicles Nat. Neuroscience 2010; 13(7):845-51.
Cole, AR. PCTK proteins: the forgotten brain kinases? Neurosignals 2009; 17(4):288-97.
Cole AR, Soutar MPM, Rembutsu M, VanAalten L, Hastie CJ, McLauchlan H, Peggie MW, Balastik M, Lu KP and Sutherland C. Relative resistance of Cdk5-phosphorylated CRMP2 to dephosphorylation. J. Biol. Chem. 2008; 283(26):18227-37.
Cole AR, Noble W, van Aalten L, Plattner F, Meimaridou R, Hogan D, LaFrancois J, Taylor M, Gunn-Moore F, Verkhratsky A, Oddo S, La Ferla F, Duff K, Giese KP, Dineley KT, Richardson JC, Yan SD, Hanger DP, Allan SM and Sutherland C. Collapsin response mediator protein-2 hyperphosphorylation is an early event in Alzheimer’s disease progression. J. Neurochem. 2007; 103(3):1132-44.
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