GSK-3β 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-3β inhibition reverses axonal transport defects and behavioural phenotypes in Drosophila. Molecular Psychiatry, 9, (5), 522-530. (doi:10.1038/sj.mp.4001483). (PMID:14993907).

Download

Full text not available from this repository.

Description/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-3beta (GSK-3beta) enhances and two GSK-3beta 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-3beta might have potential therapeutic benefits in tauopathies.

Item Type: Article
ISSNs: 1359-4184 (print)
1359-4184 (electronic)
Keywords: alzheimer's disease, axonal transport, drosophila, gsk-3beta, lithium, tau
Subjects: Q Science > QR Microbiology
R Medicine > RB Pathology
Divisions: University Structure - Pre August 2011 > School of Biological Sciences
ePrint ID: 56491
Date Deposited: 08 Aug 2008
Last Modified: 27 Mar 2014 18:39
URI: http://eprints.soton.ac.uk/id/eprint/56491

Actions (login required)

View Item View Item