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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Axonal Transport / drug effects
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Axonal Transport / physiology*
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Axons / drug effects
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Axons / metabolism
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Drosophila Proteins / antagonists & inhibitors
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Drosophila Proteins / genetics
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Drosophila Proteins / physiology*
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Drosophila melanogaster / genetics
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Drosophila melanogaster / metabolism*
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Enzyme Inhibitors / pharmacology*
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Glycogen Synthase Kinase 3 / antagonists & inhibitors
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Glycogen Synthase Kinase 3 / genetics
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Glycogen Synthase Kinase 3 / physiology*
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Humans
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Larva
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Lithium Chloride / pharmacology
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Locomotion / drug effects
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Locomotion / physiology*
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Phosphorylation / drug effects
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Protein Processing, Post-Translational* / drug effects
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Recombinant Fusion Proteins / antagonists & inhibitors
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Recombinant Fusion Proteins / physiology
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Tauopathies / drug therapy
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Tauopathies / physiopathology
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Thiazoles / pharmacology
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Urea / analogs & derivatives*
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Urea / pharmacology
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tau Proteins / genetics
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tau Proteins / physiology*
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tau Proteins / toxicity
Substances
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Drosophila Proteins
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Enzyme Inhibitors
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Recombinant Fusion Proteins
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Thiazoles
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tau Proteins
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N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea
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Urea
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Sgg protein, Drosophila
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Glycogen Synthase Kinase 3
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Lithium Chloride