Projects

GSK-3β (glycogen synthase kinase 3 β) is a key coordinator of neuronal development, because it can be triggered by wide a number of signalling cascades which it then translates into changes in neuronal cell behaviour by directly regulating the cytoskeleton (B). 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. We study which regulators mediate GSK-3β activity to influence neuronal development; a fundamental question which could provide the basis for refined therapies.

For this, we pioneered the use of Drosophila primary neurons for the study of GSK-3β, a powerful tool enabled us to analyse the functions of 15 microtubule (MT)- and 15 actin-binding and -regulating proteins (Hahn et al., PLoS Genet, 2021; Hahn et al., Neural dev. 2019; Qu*, Hahn* et al., eLife, 2019; Qu*, Hahn* et al. Mol Biol Cell, 2017). Using global up- or down-regulation of GSK-3β, we demonstrated that GSK-3β is a key regulator of axonal microtubules in fly and rat primary neurons. This work is funded by the 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.