Human Wild-Type Tau Interacts with wingless Pathway Components and Produces Neurofibrillary Pathology in Drosophila

Jackson, George R.; Wiedau‐Pazos, Martina; Sang, Tzu-Kang; Wagle, Naveed; Brown, Carlos A; Massachi, Sasan; Geschwind, Daniel H.

doi:10.1016/s0896-6273(02)00706-7

Cited by 468 publications

(432 citation statements)

References 89 publications

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“…125 Active GSK-3 was detected in pretangle neurons and NFTs in AD brains, and coexpression of the GSK-3 homolog shaggy with tau led to tau hyperphosphorylation, filamentous tau aggregation, and neurotoxicity in Drosophila fruit fly. 126,127 In line with these findings, GSK-3␤ overexpressing transgenic mice showed increased tau phosphorylation and deficits in spatial memory. 128,129 Tau phosphorylation by GSK-3 can be enhanced by A␤ -treatment, which thus provides a possible link between tau and A␤ pathology.…”

Section: Antiphosphorylation Strategiesmentioning

confidence: 58%

Tau-Based Treatment Strategies in Neurodegenerative Diseases

2008

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Summary:Neurofibrillary tangles are a characteristic hallmark of Alzheimer's and other neurodegenerative diseases, such as Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). These diseases are summarized as tauopathies, because neurofibrillary tangles are composed of intracellular aggregates of the microtubule-associated protein tau. The molecular mechanisms of tau-mediated neurotoxicity are not well understood; however, pathologic hyperphosphorylation and aggregation of tau play a central role in neurodegeneration and neuronal dysfunction. The present review, therefore, focuses on therapeutic approaches that aim to inhibit tau phosphorylation and aggregation or to dissolve preexisting tau aggregates. Further experimental therapy strategies include the enhancement of tau clearance by activation of proteolytic, proteasomal, or autophagosomal degradation pathways or anti-tau directed immunotherapy. Hyperphosphorylated tau does not bind microtubules, leading to microtubule instability and transport impairment. Pharmacological stabilization of microtubule networks might counteract this effect. In several tauopathies there is a shift toward four-repeat tau isoforms, and interference with the splicing machinery to decrease four-repeat splicing might be another therapeutic option.

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Section: Antiphosphorylation Strategiesmentioning

confidence: 58%

Tau-Based Treatment Strategies in Neurodegenerative Diseases

2008

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“…45 In these models, death was correlated with the time-dependent overexpression of exogenous tau, and with coincident emergence of phosphorylated and aggregated tau structures 22,45,23 or, as in the Drosophila model, with the level of expression of the transgene. 24 We estimated that the expression level of exogenous tau (1-441) and tau (1-230) in CGNs was Btwo-fold the endogenous level of tau (not shown). It should be noted that the level of expression was heterogeneous and varied between individual cells, some of which may express significantly higher amounts of the protein than the immunoblot results indicate.…”

Section: Discussionmentioning

confidence: 95%

“…[22][23][24] Furthermore, the overexpression of pseudohyperphosphorylated tau in neuronal cells causes apoptotic death. 25 We therefore monitored the neuronal viability ( Figure 4b) and the myc-tau expression (Figure 4c Moreover, the expression of exogenous tau proteins (tau 1-441 and tau 1-230) in CGNs was not accompanied by an increase in the AD-phosphorylated epitopes on tau -an event that could impair neuronal viability 25 -as detected with distinct specific antibodies such as AT8, PHF1, and PHF6 ( Figure 4d).…”

Section: Myc-epitope Tags Do Not Impair the Property Of Exogenous Taumentioning

confidence: 99%

Role of N-terminal tau domain integrity on the survival of cerebellar granule neurons

et al. 2003

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Although the role of the microtubule-binding domain of the tau protein in the modulation of microtubule assembly is widely established, other possible functions of this protein have been poorly investigated. We have analyzed the effect of adenovirally mediated expression of two fragments of the Nterminal portion -free of microtubule-binding domain -of the tau protein in cerebellar granule neurons (CGNs). We found that while the expression of the tau (1-230) fragment, as well as of full-length tau, inhibits the onset of apoptosis, the tau (1-44) fragment exerts a powerful toxic action on the same neurons. The antiapoptotic action of tau (1-230) is exerted at the level of Akt-mediated activation of the caspase cascade. On the other hand, the toxic action of the (1-44) fragment is not prevented by inhibitors of CGN apoptosis, but is fully inhibited by NMDA receptor antagonists. These findings point to a novel, physiological role of the N-terminal domain of tau, but also underlay that its possible proteolytic truncation mediated by apoptotic proteases may generate a highly toxic fragment that could contribute to neuronal death.

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“…Defects in the wnt signaling pathway have also been postulated to contribute to the pathogenesis of AD (De Ferrari and Inestrosa 2000;Jackson et al 2002). How wnt signaling may play a role in AD pathology remains to be elucidated, but it can be speculated that events leading to a decrease in GSK3b/axin complex formation, and ultimately axin levels, may allow GSK3b to aberrantly phosphorylate tau at primed sites (such as the epitope recognized by AT180) , which are increased in AD brain Spillantini et al 1996;Cairns et al 1997), and thus contribute to tau dysfunction and pathology.…”

Section: Discussionmentioning

confidence: 99%

Axin negatively affects tau phosphorylation by glycogen synthase kinase 3β

Stoothoff¹,

Bailey²,

Mi³

et al. 2002

Journal of Neurochemistry

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Glycogen synthase kinase 3b (GSK3b) is an essential protein kinase that regulates numerous functions within the cell. One critically important substrate of GSK3b is the microtubuleassociated protein tau. Phosphorylation of tau by GSK3b decreases tau-microtubule interactions. In addition to phosphorylating tau, GSK3b is a downstream regulator of the wnt signaling pathway, which maintains the levels of b-catenin. Axin plays a central role in regulating b-catenin levels by bringing together GSK3b and b-catenin and facilitating the phosphorylation of b-catenin, targeting it for ubiquitination and degradation by the proteasome. Although axin clearly facilitates the phosphorylation of b-catenin, its effects on the phosphorylation of other GSK3b substrates are unclear.Therefore in this study the effects of axin on GSK3b-mediated tau phosphorylation were examined. The results clearly demonstrate that axin is a negative regulator of tau phosphorylation by GSK3b. This negative regulation of GSK3b-mediated tau phosphorylation is due to the fact that axin efficiently binds GSK3b but not tau and thus sequesters GSK3b away from tau, as an axin mutant that does not bind GSK3b did not inhibit tau phosphorylation by GSK3b. This is the first demonstration that axin negatively affects the phosphorylation of a GSK3b substrate, and provides a novel mechanism by which tau phosphorylation and function can be regulated within the cell.

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Human Wild-Type Tau Interacts with wingless Pathway Components and Produces Neurofibrillary Pathology in Drosophila

Cited by 468 publications

References 89 publications

Tau-Based Treatment Strategies in Neurodegenerative Diseases

Tau-Based Treatment Strategies in Neurodegenerative Diseases

Role of N-terminal tau domain integrity on the survival of cerebellar granule neurons

Axin negatively affects tau phosphorylation by glycogen synthase kinase 3β

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