TY - JOUR

T1 - GSK-3beta inhibition reverses axonal transport defects and behavioural phenotypes in Drosophila

AU - Mudher, A

AU - Shepherd, D

AU - Newman, T A

AU - Mildren, P

AU - Jukes, J P

AU - Squire, A

AU - Mears, A

AU - Berg, S

AU - MacKay, D

AU - Asuni, A A

AU - Bhat, R

AU - Lovestone, S

PY - 2004/5

Y1 - 2004/5

N2 - 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.

AB - 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.

KW - Animals

KW - Axonal Transport/drug effects

KW - Axons/drug effects

KW - Drosophila Proteins/antagonists & inhibitors

KW - Drosophila melanogaster/genetics

KW - Enzyme Inhibitors/pharmacology

KW - Glycogen Synthase Kinase 3/antagonists & inhibitors

KW - Humans

KW - Larva

KW - Lithium Chloride/pharmacology

KW - Locomotion/drug effects

KW - Phosphorylation/drug effects

KW - Protein Processing, Post-Translational/drug effects

KW - Recombinant Fusion Proteins/antagonists & inhibitors

KW - Tauopathies/drug therapy

KW - Thiazoles/pharmacology

KW - Urea/analogs & derivatives

KW - tau Proteins/genetics

U2 - 10.1038/sj.mp.4001483

DO - 10.1038/sj.mp.4001483

M3 - Article

C2 - 14993907

VL - 9

SP - 522

EP - 530

JO - Molecular Psychiatry

JF - Molecular Psychiatry

SN - 1359-4184

IS - 5

ER -