Cited by 266Alzheimer's disease research and treatmentsAmyotrophic Lateral Sclerosis ResearchNeurobiology and Insect Physiology Research

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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, Lovestone, S·2004·Molecular Psychiatry

DOI 10.1038/sj.mp.4001483

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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.

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Authors: 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., & Lovestone, S.
Affiliations: King's College London (GB)
University of Southampton (GB)
AstraZeneca (Sweden) (SE)
Corresponding author: Lovestone, S
ORCID: Shepherd, D
Newman, T A
Squire, A
Berg, S
Asuni, A A
Bhat, R
Lovestone, S
Venue: Molecular Psychiatry
Publisher: Springer Science and Business Media LLC
Published: 2004-03-02
Volume: 9
Issue: 5
Pages: 522-530
ISSN: 1359-4184 (ISSN-L)
1476-5578
DOI: 10.1038/sj.mp.4001483
OpenAlex: W2020815630
Cited by: 265
References: 35
Citations by year: 2026: 3 · 2025: 9 · 2024: 6 · 2023: 5 · 2022: 9 · 2021: 7 · 2020: 11 · 2019: 9 · 2018: 9 · 2017: 11 · 2016: 11 · 2015: 9 · 2014: 18 · 2013: 14 · 2012: 22
FWCI: 9.66
Type: journal article
Language: en
Update notices: erratum (2004-07-26)
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Molecular Psychiatry (publishedVersion)
PubMed (publishedVersion)
ePrints Soton (University of Southampton) (submittedVersion)
Research Portal (King's College London) (submittedVersion)
Funders: Wellcome Trust
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurobiology and Insect Physiology Research
Keywords: tauopathy, glycogen synthase kinase-3β, GSK-3β inhibition, tau phosphorylation, axonal transport, vesicle aggregation, locomotor dysfunction, motor neurons, lithium, AR-A014418, Alzheimer's disease, frontotemporal dementia, neurodegeneration, Drosophila model
MeSH terms: Animals, Axons, Axonal Transport, Drosophila melanogaster, Enzyme Inhibitors, Humans, Larva, Locomotion, Phosphorylation, Protein Processing, Post-Translational, Recombinant Fusion Proteins, Thiazoles, Urea, tau Proteins, Lithium Chloride, Tauopathies, Drosophila Proteins, Glycogen Synthase Kinase 3

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

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