Glycogen Synthase Kinase-3β Phosphorylates Protein Tau and Rescues the Axonopathy in the Central Nervous System of Human Four-repeat Tau Transgenic Mice

Spittaels, Kurt; Haute, Chris Van den; Dorpe, Jo Van; Geerts, Hugo; Mercken, Marc; Bruynseels, Koen; Lasrado, Reena; Vandezande, Kris; Laenen, Isabelle; Boon, Tim; Lint, Johan Van; Vandenheede, Jackie R.; Moechars, Diederik; Loos, Ruth J.F.; Leuven, Freddy Van

doi:10.1074/jbc.m006219200

Cited by 306 publications

(302 citation statements)

References 84 publications

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“…However, a report demonstrating that increased GSK3b expression in a mouse model of tau overexpression decreased the axonopathy may seem to indicate that GSK3b may not play a role in the processes which lead to tau pathology and neuronal dysfunction in AD (Spittaels et al 2000). However, when tau is overexpressed in mice, axonopathy often occurs, which is likely due to the fact that tau inhibits kinesin-dependent processes leading to the inappropriate accumulation of proteins and organelles (Ebneth et al 1998;Stamer et al 2002).…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

“…GSK3b phosphorylates tau on numerous sites, including both primed and unprimed (which are located in proline rich regions) epitopes Lovestone et al 1994;Spittaels et al 2000). Phosphorylation of tau by GSK3b, like many other kinases, decreases the ability of tau to bind and stabilize microtubules (Lovestone et al 1996;Wagner et al 1996;Sang et al 2001).…”

mentioning

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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“…Our tau-4R/2N transgenic mice developed severe axonopathy due to axonal dilatations (spheroids) with Wallerian degeneration and severe motor problems but no tau aggregates (16). The axonopathy was fully corrected by co-expression of GSK-3␤, demonstrating for the first time in vivo that phosphorylation of tau is essential to prevent "clogging" of the axons (17), as in cells (18) by reducing binding of tau to microtubules. Expression of mutant tau in transgenic mice produced tau aggregates (19 -22; reviewed in Ref.…”

mentioning

confidence: 82%

Changed Conformation of Mutant Tau-P301L Underlies the Moribund Tauopathy, Absent in Progressive, Nonlethal Axonopathy of Tau-4R/2N Transgenic Mice

Terwel

Lasrado

Snauwaert

et al. 2005

Journal of Biological Chemistry

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Protein tau-3R/4R isoform ratio and phosphorylation regulates binding to microtubules and, when disturbed by aging or mutations, results in diverse tauopathies and in neurodegeneration. The underlying mechanisms were studied here in three transgenic mouse strains with identical genetic background, all expressing the tau-4R/2N isoform driven specifically in neurons by the thy1 gene promoter. Two strains, expressing human tau-4R/2N or mutant tau-4R/2N-P301L at similar, moderate levels, developed very different phenotypes. Tau-4R/2N mice became motor-impaired already around age 6-8 weeks, accompanied by axonopathy (dilatations, spheroids), but no tau aggregates, and surviving normally. In contrast, tau-P301L mice developed neurofibrillary tangles from age 6 months, without axonal dilatations and, despite only minor motor problems, all succumbing before the age of 13 months. The third strain, obtained by tau knock-out/knock-in (tau-KOKI), expressed normal levels of wild-type human tau-4R/2N replacing all mouse tau isoforms. Tau-KOKI mice survived normally with minor motor problems late in life and without any obvious pathology. Biochemically, a fraction of neuronal tau in aging tau-P301L mice was hyperphosphorylated concomitant with conformational changes and aggregation, but overall, tau-4R/2N was actually more phosphorylated than tau-P301L. Significantly, tau with changed conformation and with hyperphosphorylation colocalized in the same neurons in aging tau-P301L mice. Taken together, we conclude that excessive binding of tau-4R/2N as opposed to reduced binding of tau-P301L to microtubules is responsible for the development of axonopathy and tauopathy, respectively, in tau-4R/2N and tau-P301L mice and that the conformational change of tau-P301L is a major determinant in triggering the tauopathy.

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“…Also, overexpression of shaggy, the fly homologue of glycogen synthase kinase-3␤ (GSK-3␤) and a candidate kinase for tau phosphorylation, caused increased neurodegeneration, increased tau phosphorylation, and the appearance of filamentous tau aggregates (30). In contrast, in tau Tg mice, overexpression of GSK-3␤ alleviated transgeneinduced motor neuron defects and axonopathy (31), even though GSK-3␤ overexpression increases tau phosphorylation (31)(32)(33). Thus, the role of phosphorylation in tau-induced neurotoxicity is unclear.…”

Section: Discussionmentioning

confidence: 99%

Neurodegeneration and defective neurotransmission in a Caenorhabditis elegans model of tauopathy

Kraemer

Zhang

Leverenz

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

336

284

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Frontotemporal dementia with parkinsonism chromosome 17 type (FTDP-17) is caused by mutations in MAPT, the gene encoding tau. FTDP-17 begins with executive function deficits and other abnormal behaviors, which progress to dementia. Neurodegenerative changes include accumulation of aggregated tau as neuronal and glial fibrillary tangles. Aggregated tau is seen in numerous other neurodegenerative diseases, including Alzheimer's disease (AD). We expressed normal and FTDP-17 mutant human tau (mutations P 301 L and V 337 M ) in Caenorhabditis elegans to model tauopathy disorders. Tau pan-neuronal expression caused progressive uncoordinated locomotion (Unc), characteristic of nervous system defects in worms. Subsequently, insoluble tau accumulates and both soluble and insoluble tau is phosphorylated at many of the sites hyperphosphorylated in FTDP-17, AD, and other tauopathies. Substantial neurodegeneration, seen as bulges and gaps in nerve cords followed by loss of neurons, occurs after insoluble tau begins to accumulate. Axons show vacuoles, membranous infoldings, and whorls with associated amorphous tau accumulations and abnormal tau-positive aggregates. FTDP-17 mutation lines had a more severe Unc phenotype, accumulated more insoluble tau at a younger age, were more resistant to cholinergic inhibitors, and had more severe axonal degeneration when compared with lines expressing normal tau. The Unc phenotype is caused by a presynaptic defect. Postsynaptic transmission is intact. This transgenic model will enable mechanistic dissection of tau-induced neurodegeneration and identification of genes and compounds that inhibit pathological tau formation.A bnormally aggregated tau accumulates as neurofibrillary tangles and other lesions in many neurodegenerative diseases including Alzheimer's disease (AD) and frontotemporal dementia with parkinsonism chromosome 17 type (FTDP-17). For AD and most tauopathies, the role tau plays in disease initiation and progression is unknown. However, in FTDP-17, mutations in MAPT, the gene encoding tau, cause the disease (1-3), albeit by incompletely understood mechanisms. One hypothesis is that microtubule (MT)-mediated axonal transport is disrupted, an idea based on the reduced binding affinity of mutant tau for MTs (4). Another hypothesis is that aggregated tau is deleterious to cells, and in FTDP-17, aggregation is driven by either increased free tau concentrations (4) or mutationinduced acceleration of self-aggregation (5, 6). The critical toxic aggregate may be a dimer, a more extensive aggregate, tau filaments, or the end-stage tangles. The phosphorylation state of tau may also be important, as pathologic insoluble tau is hyperphosphorylated (7).To identify critical steps in tau-induced neurodegeneration, we generated a MAPT transgenic (Tg) Caenorhabditis elegans model of FTDP-17. Pan-neuronal expression of normal or FTDP-17 mutant MAPT resulted in altered behavior (uncoordinated movement), accumulation of insoluble phosphorylated tau, age-dependent loss of axons and neurons, and s...

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Glycogen Synthase Kinase-3β Phosphorylates Protein Tau and Rescues the Axonopathy in the Central Nervous System of Human Four-repeat Tau Transgenic Mice

Cited by 306 publications

References 84 publications

Axin negatively affects tau phosphorylation by glycogen synthase kinase 3β

Axin negatively affects tau phosphorylation by glycogen synthase kinase 3β

Changed Conformation of Mutant Tau-P301L Underlies the Moribund Tauopathy, Absent in Progressive, Nonlethal Axonopathy of Tau-4R/2N Transgenic Mice

Neurodegeneration and defective neurotransmission in a Caenorhabditis elegans model of tauopathy

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