Sequential phosphorylation of Tau by glycogen synthase kinase‐3β and protein kinase A at Thr212 and Ser214 generates the Alzheimer‐specific epitope of antibody AT100 and requires a paired‐helical‐filament‐like conformation

Zheng-Fischhöfer, Qingyi; Biernat, Jacek; Mandelkow, Eva‐Maria; Illenberger, Susanne; Godemann, Robert

doi:10.1046/j.1432-1327.1998.2520542.x

Cited by 302 publications

(252 citation statements)

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“…What could be the kinases responsible for the abnormal phosphorylation of Tau proteins and especially at site recognised by one of the only antibodies that specially recognises PHF-Tau, AT100 antibody? AT100 binds to a conformation epitope including phosphorylated Thr212 and Ser214 [2]. Sequential phosphorylation of Tau protein by GSK3L and PKA has been reported to generate this epitope in vitro [2].…”

Section: Discussionmentioning

confidence: 99%

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Modelling Alzheimer‐specific abnormal Tau phosphorylation independently of GSK3β and PKA kinase activities

et al. 2002

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In Alzheimer's disease, neurofibrillary degeneration results from the aggregation of abnormally phosphorylated Tau proteins into paired helical filaments. These Tau variants displayed specific epitopes that are immunoreactive with antiphospho-Tau antibodies such as AT100. As shown in in vitro experiments, glycogen synthase kinase 3 L L (GSK3L L) and protein kinase A (PKA) may be key kinases in these phosphorylation events. In the present study, Tau was microinjected into Xenopus oocytes. Surprisingly, in this system, AT100 was generated without any GSK3L L and PKA contribution during the progesterone or insulin-induced maturation process. Our results demonstrate that a non-modified physiological process in a cell model can generate the most specific Alzheimer epitope of Tau pathology. ß

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Section: Discussionmentioning

confidence: 99%

“…AT100 was used to detect abnormal Tau phosphorylation [2]. Finally, M19G is a well-characterised anti-serum, directed against the ¢rst 19 amino acids of the tau sequence encoded by exon 1 [18] that recognises its epitope independently of the Tau phosphorylation state.…”

Section: Antibodiesmentioning

confidence: 99%

Modelling Alzheimer‐specific abnormal Tau phosphorylation independently of GSK3β and PKA kinase activities

et al. 2002

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“…Where necessary, breakdown products were removed using the additional gel filtration column Superdex G75 with PBS buffer. In the experimental construct used in our study, all these residues were exchanged for E to generate the pseudophosphorylated protein hTau40 AT8/AT100/PHF‐1 (Zheng‐Fischhofer et al ., 1998)—in the case of AT8 S 199 , S 202 , and T 205 (Biernat et al ., 1992), for AT100 it is T 212 and S 214 and for PHF‐1 it is S 396 and S 404 .…”

Section: Methodsmentioning

confidence: 99%

Interplay of pathogenic forms of human tau with different autophagic pathways

et al. 2017

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SummaryLoss of neuronal proteostasis, a common feature of the aging brain, is accelerated in neurodegenerative disorders, including different types of tauopathies. Aberrant turnover of tau, a microtubule‐stabilizing protein, contributes to its accumulation and subsequent toxicity in tauopathy patients’ brains. A direct toxic effect of pathogenic forms of tau on the proteolytic systems that normally contribute to their turnover has been proposed. In this study, we analyzed the contribution of three different types of autophagy, macroautophagy, chaperone‐mediated autophagy, and endosomal microautophagy to the degradation of tau protein variants and tau mutations associated with this age‐related disease. We have found that the pathogenic P301L mutation inhibits degradation of tau by any of the three autophagic pathways, whereas the risk‐associated tau mutation A152T reroutes tau for degradation through a different autophagy pathway. We also found defective autophagic degradation of tau when using mutations that mimic common posttranslational modifications in tau or known to promote its aggregation. Interestingly, although most mutations markedly reduced degradation of tau through autophagy, the step of this process preferentially affected varies depending on the type of tau mutation. Overall, our studies unveil a complex interplay between the multiple modifications of tau and selective forms of autophagy that may determine its physiological degradation and its faulty clearance in the disease context.

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“…cAMP-dependent protein kinase A (PKA) has been shown to phosphorylate tau at S262/S356 and S214 in vitro and in vivo. 102,103 Phosphorylation by PKA results in reduced microtubule-binding affinity and promotes the subsequent phosphorylation of different diagnostic phospho-epitopes. PKA phosphorylation at S214 is required to prime tau for its sequential phosphorylation by GSK-3␤, thereby giving rise to the AD-specific AT100 phospho-epitope.…”

Section: Antiphosphorylation Strategiesmentioning

confidence: 99%

“…PKA phosphorylation at S214 is required to prime tau for its sequential phosphorylation by GSK-3␤, thereby giving rise to the AD-specific AT100 phospho-epitope. 102 Activation of PKA by forskolin resulted in spatial memory deficits in rats. 103 Isoquinoline sulfonamide derivatives and staurosporines are known to inhibit PKA with low selectivity and also affect PKG, PKC, and the myosin light chain kinase (MLCK).…”

Section: Antiphosphorylation Strategiesmentioning

confidence: 99%

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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Sequential phosphorylation of Tau by glycogen synthase kinase‐3β and protein kinase A at Thr212 and Ser214 generates the Alzheimer‐specific epitope of antibody AT100 and requires a paired‐helical‐filament‐like conformation

Cited by 302 publications

References 2 publications

Modelling Alzheimer‐specific abnormal Tau phosphorylation independently of GSK3β and PKA kinase activities

Modelling Alzheimer‐specific abnormal Tau phosphorylation independently of GSK3β and PKA kinase activities

Interplay of pathogenic forms of human tau with different autophagic pathways

Tau-Based Treatment Strategies in Neurodegenerative Diseases

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