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), 1-9. (doi:10.1038/sj.mp.4001483).
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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.
|Digital Object Identifier (DOI):||doi:10.1038/sj.mp.4001483|
|Keywords:||alzheimer’s disease, axonal transport, Ddrosophila, GSK-3b, lithium, tau|
|Subjects:||R Medicine > RB Pathology
R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
|Divisions :||University Structure - Pre August 2011 > School of Biological Sciences
|Accepted Date and Publication Date:||
|Date Deposited:||28 Mar 2006|
|Last Modified:||31 Mar 2016 11:45|
|RDF:||RDF+N-Triples, RDF+N3, RDF+XML, Browse.|
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