Coexpression of GSK-3β Corrects Phenotypic Aberrations of Dorsal Root Ganglion Cells, Cultured from Adult Transgenic Mice Overexpressing Human Protein tau

Nuydens, Rony; Kieboom, Gerd Van Den; Nolten, Christ; Verhulst, C.; Osta, Peter Van; Spittaels, Kurt; Haute, Chris Van den; Feyter, E. De; Geerts, Hugo; Leuven, Fred Van

doi:10.1006/nbdi.2001.0454

Cited by 26 publications

(19 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There may be two possible mechanisms by which tau mediates this effect: it could detach kinesins and their cargoes from microtubules (possibly by competing for microtubule binding as previously suggested 6 ) or it could reduce kinesin's ATPase activity, 5 and therefore directly reduce the speed of movement such that cargo eventually slow down and get stuck in vesicular aggregations. 7 The fact that overexpression of tau did not affect the actual speed of GFP-tagged vesicles in our system suggests that the former mechanism is operating in this model and that the aggregated vesicles probably represent those that are bound to kinesin but are unable to attach themselves to microtubules. In other words, tau does not actually slow kinesin and its cargoes, but causes cargoes to become detached from microtubules, and hence in this unattached state to aggregate into the pile-ups observed in this study.…”

Section: Tau Effects On Axonal Transportmentioning

confidence: 65%

“…25 An important question is whether this increase in phosphorylation is a primary pathogenic event 28 or whether it is a compensatory process to some other process-perhaps an increase in the level of tau expression. 24 Compensatory tau phosphorylation would be supported by the findings of others, 7,26 who showed that increased phosphorylation of tau rescued the axonopathy and axonal transport disruption induced by overexpression of wt tau in a murine model. However, our findings argue against this as reducing phosphorylation of tau even in those animals that express tau alone reduces axonal transport defects, suggesting that it is not just prolonged and induced hyperphosphorylation (as in the vGFP Â tau/sgg* co-expressing animals) but endogenous phosphorylation (which would have occurred in vGFP Â tau animals) that is deleterious.…”

Section: Tau Effects On Axonal Transportmentioning

confidence: 78%

mentioning

confidence: 99%

“…In vitro studies have shown that tau interferes with kinesin activation 5 and disrupts the transport of various kinesin cargoes. [6][7][8] Drosophila provides an excellent model organism in which to test this hypothesis, not least because there are Drosophila mutations that affect axonal transport with established phenotypes, for example, kinesin mutants, 9 dynein mutants, 10 kinesin-associated protein mutants (Sunday Driver) 11 and dynein-associated protein mutants (Roadblock). 12 Most of these mutations exhibit larval locomotor defects, which include paralysis in the posterior segments, sluggish locomotion and a characteristic curling of the posterior end called 'tail flipping' caused by paralysis of the dorsal musculature.…”

mentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2004

View full text Add to dashboard Cite

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. Keywords: Alzheimer's disease; axonal transport; Drosophila; GSK-3b; lithium; tau Tauopathies are a group of neurodegenerative diseases, including Alzheimer's disease (AD) and the fronto-temporal dementias (FTD), characterised by aggregation of the microtubule-associated protein, tau, into neurofibrillary tangles (NFTs). The finding that mutations in the tau gene give rise to familial FTD 1 proved that abnormalities in tau are sufficient to cause neurodegeneration. However, the cellular mechanisms by which tau abnormalities disrupt neuronal function and lead to neurodegeneration have not been elucidated. Furthermore, in the tauopathies at least three tau protein abnormalities are observed: hyperphosphorylation, altered expression and filament formation; and it is not clear which of these plays a primary role in the disease process and which is a secondary consequence.We have previously demonstrated that overexpression of tau causes neurodegeneration in Drosophila without forming filamentous aggregates.2 Others have subsequently confirmed and extended these findings by illustrating that overexpression of FTDP-17 mutant tau also induces neurodegeneration in Drosophila without the formation of neurofibrillary aggregates. 3More recently it has been shown that hyperphosphorylation of overexpressed tau not only exacerbates the neurodegeneration seen with tau alone but also stimulates filament formation leading to NFT formation in Drosophila.4 These findings collectively demonstrate that although hyperphosphorylation, and possibly filament formation, can exacerbate taumediated neurodegeneration, overexpression of wildtype (wt) tau alone is sufficient to cause neurodegeneration. The molecular events underlying this have not been elucidated.There are many ways by which tau overexpression could disrupt neuronal homeostasis and cause neu...

show abstract

Section: Tau Effects On Axonal Transportmentioning

confidence: 65%

Section: Tau Effects On Axonal Transportmentioning

confidence: 78%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2004

View full text Add to dashboard Cite

show abstract

“…As was previously shown, overexpression of tau in cultured cells led to disturbance of the axonal transport (Ebneth et al, 1998;Trinczek et al, 1999), and to axonopathy and motor deficiencies in tau transgenic mice (Spittaels et al, 1999). The deficient anterograde transport together with the axonopathy was restored to almost normal when GSK-3 levels were increased by crossing these mice with GSK-3 transgenic animals (Spittaels et al, 2000;Nuydens et al, 2002). In addition to tau, GSK-3 has also been shown, in vitro, to phosphorylate kinesin light chains, resulting in a release of cargo organelles and thus disturbance of the axonal transport (Morfini et al, 2001).…”

Section: Discussionmentioning

confidence: 76%

Role of tau phosphorylation by glycogen synthase kinase-3β in the regulation of organelle transport

Tatebayashi¹,

Haque²,

Tung³

et al. 2004

Journal of Cell Science

View full text Add to dashboard Cite

Anterograde organelle transport is known to be inhibited by overexpression of the microtubule-associated protein tau in cultured cells. However, the molecular mechanism regulating this function of tau protein has not previously been understood. We found that in PC12 cells treated with NGF or fibroblast growth factor-2, glycogen synthase kinase-3β and tau were upregulated simultaneously from around day 2 of differentiation, with increasing glycogen synthase kinase-3-mediated tau phosphorylation. This phosphorylation did not alter tau's ability to bind to microtubules but appeared to be required for the maintenance of the anterograde organelle transport in differentiated cells. Lithium, alsterpaullone or valproate, three independent glycogen synthase kinase-3 inhibitors, but not butyrolactone 1, an inhibitor of cyclin-dependent protein kinases, induced mitochondrial clustering in association with tau dephosphorylation. In CHO cells transfected with human tau441, mitochondrial clustering was found in cells in which tau was unphosphorylated. These findings raise the possibility that the phosphorylation of tau by glycogen synthase kinase-3 might be involved in the regulation of organelle transport.

show abstract

Role of GSK‐3β in Alzheimer's disease pathology

Planel

Sun

Takashima

2002

Drug Development Research

View full text Add to dashboard Cite

Glycogen synthase kinase 3b (GSK-3b) is an important regulatory kinase involved in multiple processes such as metabolic control, embryonic development, cell death, and oncogenesis. It has been found to interact with many molecules associated with Alzheimer's disease (AD) such as the microtubule-associated protein tau, presenilin 1, the amyloid-b peptide, the amyloid precursor protein, and acetylcholine. Furthermore, GSK-3b might be involved in brain aging and longevity. As GSK-3b is associated with so many components of AD pathology, we review the current data on the role of this kinase in tau hyperphosphorylation, then look at its association with AD-related molecules and pathways, and finally discuss its involvement in cell death and aging. We attempt to integrate all these data to arrive at the proposition that GSK-3b is a pivotal molecule in the evolution of AD and that developing drugs directed at this kinase might prove to be beneficial in the treatment of this devastating disease. Drug Dev.

show abstract

Coexpression of GSK-3β Corrects Phenotypic Aberrations of Dorsal Root Ganglion Cells, Cultured from Adult Transgenic Mice Overexpressing Human Protein tau

Cited by 26 publications

References 40 publications

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

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

Role of tau phosphorylation by glycogen synthase kinase-3β in the regulation of organelle transport

Role of GSK‐3β in Alzheimer's disease pathology

Contact Info

Product

Resources

About