Projects

GSK-3β (glycogen synthase kinase 3β) is a key coordinator of neuronal development, because it can be triggered by a wide range of signalling cascades which it then translates into changes in neuronal cell behaviour by directly regulating the cytoskeleton. GSK-3β is essential for almost all steps of neuronal development and hyperactive GSK-3β is linked to neurodegenerative diseases (i.e. Alzheimer's, Parkinson's disease), schizophrenia, bipolar disorder, autism, neuropathies, and impaired regeneration after injury, making it a promising target for therapy. So far, however, therapeutic strategies manipulating GSK-3β have failed because their application was too general. Recent work from our laboratory demonstrated that both increased and decreased GSK-3β activity disrupt axonal microtubule organisation, revealing that neuronal function depends on a tightly balanced level of kinase activity (Voelzmann et al. PNAS, 2026). Using Drosophila and rat neurons, we identified the microtubule regulators Shot and Tau as key downstream effectors through which GSK-3β controls the maintenance of parallel axonal microtubule bundles. GSK-3β regulates the interaction of Shot and Tau with microtubules and the plus-end tracking protein Eb1; misregulation of this pathway causes microtubule unbundling, axonal swellings, and cytoskeletal disorganisation. These findings provide a mechanistic explanation for the link between altered GSK-3β activity and neurodegeneration, and may help explain why broad GSK-3β inhibition has shown limited success in clinical trials.

Building on these discoveries, we are currently developing novel experimental tools to measure and manipulate GSK-3β activity with high spatial and temporal precision in living neurons. These approaches will enable us to determine how local pools of GSK-3β regulate cytoskeletal organisation in distinct subcellular compartments, such as growth cones, axon shafts and synapses. By moving beyond global gain- and loss-of-function approaches, we aim to identify context-specific mechanisms of GSK-3β signalling that could ultimately provide the foundation for more targeted and effective therapeutic strategies. 

This work is funded by the BBSRC, Leverhulme and Wellcome Trust and the Academy of Medical Sciences.

Neurofibromatosis type 1 is among the most common monogenetic disorders of humans and is caused by loss of neurofibromin (Nf1), a highly conserved protein that serves as a GTPase-Activating Protein (GAP) for Ras. Loss of Nf1 leads to cognitive and behavioural deficits as well as electrophysiological abnormalities in patients and animal models. How cellular and molecular mechanisms drive these functional impairments is, however, largely unknown. We recently found that that loss of Nf1 leads to impaired neuronal outgrowth, defects in formation of pre-synapses, misregulation of the cytoskeleton in flies. We will use an interdisciplinary approach linking detailed cell mechanistic studies with functional, electrophysiological readouts; a crucial step towards identifying therapeutic interventions. This work is funded by the Royal Society.