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  • Original Research Article
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GSK-3β inhibition reverses axonal transport defects and behavioural phenotypes in Drosophila

Molecular Psychiatry volume 9, pages 522–530 (2004)Cite this article

A Corrigendum to this article was published on 26 July 2004

Abstract

The tauopathies are a group of disorders characterised by aggregation of the microtubule-associated protein tau and include Alzheimer's disease (AD) and the fronto-temporal dementias (FTD). We have used Drosophila to analyse how tau abnormalities cause neurodegeneration. By selectively co-expressing wild-type human tau (0N3R isoform) and a GFP vesicle marker in motorneurons, we examined the consequences of tau overexpression on axonal transport in vivo. The results show that overexpression of tau disrupts axonal transport causing vesicle aggregation and this is associated with loss of locomotor function. All these effects occur without neuron death. Co-expression of constitutively active glycogen-synthase kinase-3β (GSK-3β) enhances and two GSK-3β inhibitors, lithium and AR-A014418, reverse both the axon transport and locomotor phenotypes, suggesting that the pathological effects of tau are phosphorylation dependent. These data show that tau abnormalities significantly disrupt neuronal function, in a phosphorylation-dependent manner, before the classical pathological hallmarks are evident and also suggest that the inhibition of GSK-3β might have potential therapeutic benefits in tauopathies.

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Acknowledgements

This work was supported by the Alzheimer's Society and The Wellcome Trust. We would like to acknowledge Professor Hugh Perry and Dr Francis Chee for comments on the manuscript, and Dr Anton Page and Mr Roger Alston of the Biomedical Imaging Unit for confocal microscopy.

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Authors and Affiliations

  1. Department of Neuroscience and Old Age Psychiatry, Institute of Psychiatry, Kings College London, De Crespigny Park, London, UK

    A Mudher, D MacKay, A A Asuni & S Lovestone

  2. School of Biological Sciences, University of Southampton, Southampton, UK

    D Shepherd, T A Newman, P Mildren, J P Jukes, A Squire & A Mears

  3. AstraZeneca R&D Sodertalje, Research DMPK, Sweden

    S Berg & R Bhat

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  1. A Mudher
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Correspondence to S Lovestone.

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(Supplementary information accompanies the paper on Molecular Psychiatry website (http://www.nature.com/mp))

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Mudher, A., Shepherd, D., Newman, T. et al. GSK-3β inhibition reverses axonal transport defects and behavioural phenotypes in Drosophila. Mol Psychiatry 9, 522–530 (2004). https://doi.org/10.1038/sj.mp.4001483

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