The Alzheimer‐like phosphorylation of tau protein reduces microtubule binding and involves Ser‐Pro and Thr‐Pro motifs

Gustke, N.; Steiner, Barbara; Biernat, Jacek; Meyer, Helmut E.; Goedert, Michel; Mandelkow, Eva‐Maria

doi:10.1016/0014-5793(92)80767-b

Cited by 204 publications

(107 citation statements)

References 33 publications

(30 reference statements)

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“…Thus it appears that the phosphates on TP motifs are more labile than those on SP motifs (similar to the preference of T over S in model peptides; [l]). Note that this sequence is the reverse of the phosphorylation reaction by MAP kinase or GSK-3 where SP motifs tend to be phosphorylated before the TP motifs [17]. The experiments illustrated here were done with tau pre-phosphorylated with MAP kinase, but we note that very similar results are obtained with GSK-3.…”

Section: Ppza T55mentioning

confidence: 57%

“…Of particular interest was the fmding that certain kinases transformed tau into an 'Alzheimer-like' state, as judged by the reaction with diagnostic antibodies [4,29]. These kinases were present in normal brains, phosphorylated SP and TP motifs and thus belonged to the family of proline-directed kinases [17]. Kinases of this type were MAP kinase [lo], GSK-3 [18,22,30] cdk2 and cdk5 [41].…”

Section: Discussionmentioning

confidence: 99%

“…But it was also clear that phosphatases played an important role since efficient phosphorylation was achieved only in the presence of phosphatase inhibitors [17]. The extract by itself allowed only minimal phosphorylation (C 0.5 Pi incorporated into tau).…”

Section: Tau Phosphatase Activity In the Brain Extractmentioning

confidence: 99%

“…a new 35 kDa/41 kDa kinase) and thereby strongly decreases the interaction between tau and microtubules [5]. Both types of kinase are active in brain extracts obtained from normal or Alzheimer brains [17]. However, we noted previously that the phosphorylation by the brain extract becomes significant only when phosphatase inhibitors were added to *Corresponding author.…”

Section: Introductionmentioning

confidence: 99%

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Dephosphorylation of tau protein and Alzheimer paired helical filaments by calcmeurin and phosphatase‐2A

Drewes¹,

Mandelkow²,

Baumann³

et al. 1993

FEBS Letters

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147

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We have shown previously that brain tissue contains protein kinases which can phosphorylate tau protein to a state reminiscent of the pathological state of Alzheimer paired helical filaments (PHFs); these include proline-directed kinases which phosphorylate SP or TP motifs (such as MAP kinase and GSK-3) ; Mandelkow et al. (1992)], as well as a novel kinase which phosphorylates S262 of tau protein and thereby strongly reduces the binding of tau to microtubules [Biemat et al. (1993)]. Here we report on the corresponding phosphatases in brain which normally keep the 'pathological' sites free of phosphate. The major phosphatases acting on tau are calcineurin and PP-2A, but not PP-1. Both are present and active in brain extracts, they can dephosphorylate recombinant tau after prior phosphorylation with either MAP kinase, GSK-3, or brain extract, and the course of dephosphorylation can be monitored with antibodies diagnostic of the pathological state of tau. Both phosphatases also act directly on PHF tau isolated from Alzheimer brains.

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Section: Ppza T55mentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Tau Phosphatase Activity In the Brain Extractmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Dephosphorylation of tau protein and Alzheimer paired helical filaments by calcmeurin and phosphatase‐2A

Drewes¹,

Mandelkow²,

Baumann³

et al. 1993

FEBS Letters

Self Cite

147

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“…22,45,46 Accumulation of free tau could lead to a critical threshold level that will promote dimerization/ oligomerization leading to aggregation and the formation of largely polymers and, eventually, pathological inclusions. During this putative series of events, nitrative modification of tau may occur at one or several steps in this process with diverse consequences.…”

Section: Discussionmentioning

confidence: 99%

Nitration of Tau Protein Is Linked to Neurodegeneration in Tauopathies

Horiguchi

Uryu

Giasson

et al. 2003

The American Journal of Pathology

180

118

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Oxidative and nitrative injury is implicated in the pathogenesis of Alzheimer's disease (AD) and Down syndrome (DS), but no direct evidence links this type of injury to the formation of neurofibrillary tau lesions. To address this, we generated a monoclonal antibody (mAb), n847, which recognizes nitrated tau and ␣-synuclein. n847 detected nitrated tau in the insoluble fraction of AD, corticobasal degeneration (CBD), and Pick's disease (PiD) brains by Western blots. Immunohistochemistry (IHC) showed that n847 labeled neurons in the hippocampus and neocortex of AD and DS brains. Double-label immunofluorescence with n847 and an anti-tau antibody revealed partial co-localization of tau and n847 positive tangles, while n847 immmunofluorescence and Thioflavin-S double-staining showed that a subset of n847-labeled neurons were Thioflavin-S-positive. In addition, immuno-electron microscopy revealed that taupositive filaments in tangle-bearing neurons were also labeled by n847 and IHC of other tauopathies showed that some of glial and neuronal tau pathologies in CBD, progressive supranuclear palsy, PiD, and frontotemporal dementia with parkinsonism linked to chromosome 17 also were n847-positive. Finally, nitrated and Thioflavin-S-positive tau aggregates were generated in a oligodendrocytic cell line after treatment with peroxynitrite. Taken together, these findings imply that nitrative injury is directly linked to the formation of filamentous tau inclusions. (Am J

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Characterization of microtubule-associated proteins in teleosts

Tomasiewicz¹,

Wood²

1999

Cell Motil. Cytoskeleton

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Although microtubules are known to play an important role in many cellular processes, they have been virtually neglected in fish. In this report, microtubule‐associated proteins (MAPs) in fish (teleost) were characterized using antibodies (Abs) directed against the mammalian MAPs tau, MAP1A and B, and MAP 2. Two different populations of tau‐like proteins (TLPs) were found in fish brain using the anti‐tau Abs Tau‐1, Tau‐2, tau5', and tau3'. The TLPs that were recognized by Tau‐1, Tau‐2, and tau5' were (1) heat‐stable; (2) the same molecular weight as mammalian TLPs: 59–62 kDa; (3) not enriched in microtubules prepared from catfish brain; and (4) localized to the cell body of neurons in fish brains. While the TLPs recognized by tau3' Abs were (1) heat‐stable; (2) lower molecular weight than mammalian TLPs: 32–55 vs. 50–65 kDa; (3) enriched in microtubule fractions prepared from catfish brain, and (4) localized to the axons of neurons. These results are consistent with two different populations of TLPs being present in fish brains. While MAP2 was found to be approximately the same molecular weight, 250 kDa, in zebrafish and goldfish as in mammals and to be distributed to dendrites in the fish brain, both MAP1A and MAP1B were found to be about 25% the mass of their mammalian homologs. These results suggest that MAPS in fish have some characteristics similar to their mammalian counterparts, but also possess some unique properties that require further study to elucidate their function. Cell Motil. Cytoskeleton 44:155–167, 1999. © 1999 Wiley‐Liss, Inc.

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The Alzheimer‐like phosphorylation of tau protein reduces microtubule binding and involves Ser‐Pro and Thr‐Pro motifs

Cited by 204 publications

References 33 publications

Dephosphorylation of tau protein and Alzheimer paired helical filaments by calcmeurin and phosphatase‐2A

Dephosphorylation of tau protein and Alzheimer paired helical filaments by calcmeurin and phosphatase‐2A

Nitration of Tau Protein Is Linked to Neurodegeneration in Tauopathies

Characterization of microtubule-associated proteins in teleosts

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