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GSK-3b inhibition reverses axonal transport defects and behavioural phenotypes in Drosophila

Mudher, A., Shepherd, D., Newman, T.A., Mildren, P., Jukes, J.P., Squire, A., Mears, A., Berg, S., MacKay, D., Asuni, A.A., Bhat, R. and Lovestone, S. (2004) GSK-3b inhibition reverses axonal transport defects and behavioural phenotypes in Drosophila Molecular Psychiatry, 9, (5), pp. 522-530. (doi:10.1038/sj.mp.4001483).

Record type: Article

Abstract

The tauopathies are a group of disorders characterised by aggregation of the microtubuleassociated 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 glycogensynthase kinase-3b (GSK-3b) enhances and two GSK-3b 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-3b might have potential therapeutic benefits in tauopathies.

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e-pub ahead of print date: 2 March 2004
Published date: 2004
Keywords: alzheimer’s disease, axonal transport, Ddrosophila, GSK-3b, lithium, tau
Organisations: Biological Sciences

Identifiers

Local EPrints ID: 24170
URI: http://eprints.soton.ac.uk/id/eprint/24170
ISSN: 1359-4184
PURE UUID: 370f7817-d875-4131-9787-4a7f8f346b67

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Date deposited: 28 Mar 2006
Last modified: 17 Jul 2017 16:14

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Contributors

Author: A. Mudher
Author: D. Shepherd
Author: T.A. Newman
Author: P. Mildren
Author: J.P. Jukes
Author: A. Squire
Author: A. Mears
Author: S. Berg
Author: D. MacKay
Author: A.A. Asuni
Author: R. Bhat
Author: S. Lovestone

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