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

GSK-3b inhibition reverses axonal transport defects and behavioural phenotypes in Drosophila
GSK-3b inhibition reverses axonal transport defects and behavioural phenotypes in Drosophila
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.
alzheimer’s disease, axonal transport, Ddrosophila, GSK-3b, lithium, tau
1359-4184
522-530
Mudher, A.
ce0ccb35-ac49-4b6c-92b4-8dd5e78ac119
Shepherd, D.
a12a1d37-2cdc-47d9-84f6-efdd8096f51d
Newman, T.A.
322290cb-2e9c-445d-a047-00b1bea39a25
Mildren, P.
dc6481ba-a080-49ea-af4a-ca181c897962
Jukes, J.P.
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Squire, A.
ecbabb68-1bb5-4703-92ba-dc9e413d9080
Mears, A.
795dda89-bee7-4001-a37e-52d421ad5a34
Berg, S.
df608923-2878-4823-a8b7-02b632c26eb6
MacKay, D.
6ddf9406-f19f-4bff-9543-8fa1f445ed32
Asuni, A.A.
b1412b1b-9794-4705-aada-aed5d3da038f
Bhat, R.
e918ee68-abbc-44ce-93f0-0e978eb525d0
Lovestone, S.
482e0c1a-10cf-45fb-8631-bf32ca331104
Mudher, A.
ce0ccb35-ac49-4b6c-92b4-8dd5e78ac119
Shepherd, D.
a12a1d37-2cdc-47d9-84f6-efdd8096f51d
Newman, T.A.
322290cb-2e9c-445d-a047-00b1bea39a25
Mildren, P.
dc6481ba-a080-49ea-af4a-ca181c897962
Jukes, J.P.
fb6cdc33-fe2b-46d1-975c-b4f20675e0f2
Squire, A.
ecbabb68-1bb5-4703-92ba-dc9e413d9080
Mears, A.
795dda89-bee7-4001-a37e-52d421ad5a34
Berg, S.
df608923-2878-4823-a8b7-02b632c26eb6
MacKay, D.
6ddf9406-f19f-4bff-9543-8fa1f445ed32
Asuni, A.A.
b1412b1b-9794-4705-aada-aed5d3da038f
Bhat, R.
e918ee68-abbc-44ce-93f0-0e978eb525d0
Lovestone, S.
482e0c1a-10cf-45fb-8631-bf32ca331104

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), 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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More information

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
ORCID for T.A. Newman: ORCID iD orcid.org/0000-0002-3727-9258

Catalogue record

Date deposited: 28 Mar 2006
Last modified: 16 Mar 2024 02:52

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Contributors

Author: A. Mudher
Author: D. Shepherd
Author: T.A. Newman ORCID iD
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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