Conformation of paired helical filaments blocks dephosphorylation of epitopes shared with fetal tau except Ser199/202 and Ser202/Thr205

Gordon‐Krajcer, Wanda; Ling, Yang; Księżak-Reding, Hanna

doi:10.1016/s0006-8993(99)02391-4

Cited by 34 publications

(20 citation statements)

References 60 publications

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“…(33) Therefore, without functional Pin1, the affected pSer/Thr-Pro bonds in tau or other proteins might be accumulated in the cis isomer, which are then incorporated into NFTs. This is consistent with the findings that tau in NFTs is notoriously more difficult to dephosphorylate than fetal-like tau, (84,85) although it is not known about ths isomerization state of tau in NFTs. On the contrary, lack of proper Pin1 function may lead to further activation of mitotic kinases, including Cdc2, which may increase tau hyperphosphorylation, facilitate NFT formation, induce phosphorylation of other MPM-2 epitopes and eventually cause neuronal death.…”

Section: Introductionsupporting

confidence: 90%

Proline‐directed phosphorylation and isomerization in mitotic regulation and in Alzheimer's Disease

Liou

Vincent

2003

BioEssays

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The reversible phosphorylation of proteins on serine/threonine residues preceding proline (Ser/Thr-Pro) is a major regulatory mechanism for the control of a series of cell cycle events. Although phosphorylation is thought to regulate protein function by inducing conformational changes, little is known about most of these conformational changes and their significance. Recent studies indicate that the conformation and function of a subset of these phosphorylated proteins are controlled by the prolyl isomerase Pin1 through isomerization of specific phosphorylated Ser/Thr-Pro bonds. Furthermore, compelling evidence supports the idea that proline-directed phosphorylation and subsequent isomerization play a critical role not only in cell cycle control, but also in the development of Alzheimer's disease, where postmitotic neurons display various cell cycle markers, especially mitotic events, prior to degeneration.

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Section: Introductionsupporting

confidence: 90%

Proline‐directed phosphorylation and isomerization in mitotic regulation and in Alzheimer's Disease

Liou

Vincent

2003

BioEssays

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“…This comparison suggests that dephosphorylation of the PHF-1 epitope resulted in a faster mobility of tau. Similar observations regarding the PHF-1 epitope and its potential effect on the electrophoretic mobility of tau were reported for human tau preparations treated with alkaline phosphatase in vitro [28].…”

Section: Phosphorylated Tau In Ischemia and Reperfusionsupporting

confidence: 84%

Differential Changes in Phosphorylation of Tau at PHF-1 and 12E8 Epitopes During Brain Ischemia and Reperfusion in Gerbils

et al. 2006

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Cortical neurons are vulnerable to ischemic insult, which may cause cytoskeletal changes and neurodegeneration. Tau is a microtubule-associated protein expressed in neuronal and glial cells. We examined the phosphorylation status of tau protein in the gerbil brain cortex during 5 min ischemia induced by bilateral common carotid artery occlusion followed by reperfusion for 20 min to 7 days. Control brain homogenates contained 63, 65 and 68 kD polypeptides of tau immunoreactive with Alz 50, Tau 14 and Tau 46 antibodies raised against non-phosphorylated tau epitopes. Gerbil tau was also immunoreactive with some (PHF-1 and 12E8) but not all (AT8, AT100, AT180 and AT270) antibodies raised against phosphorylated tau epitopes. PHF-1 recognized a single 68 kD polypeptide and 12E8 bound the 63 kD polypeptide. During 5 min ischemia, PHF-1 immunoreactivity declined to 6%, then recovered to control levels after 20 min of blood recirculation and subsequently increased above control values 3 and 7 days later. In contrast, 12E8 immunoreactivity remained stable during ischemia and reperfusion. Our results suggest that the two phosphorylated epitopes of tau are regulated by different mechanisms and may play different roles in microtubule dynamics. They may also define various pools of neuronal/glial cells vulnerable to ischemia.

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“…Although the phosphoantibodies AT8, AT270, PHF-1, AD2, and Ser 422 labeled the total pool of cellular 3PO-tau, AT100 and AT180 preferentially labeled bulky aggregates. In the latter case, the densely packed tau aggregates could be less accessible to phosphatases that are specific for the AT100 and AT180 epitopes, as has been suggested before (31).…”

Section: Discussionmentioning

confidence: 60%

Removal of Pattern-breaking Sequences in Microtubule Binding Repeats Produces Instantaneous Tau Aggregation and Toxicity

Iliev

Ganesan

Bunt

et al. 2006

Journal of Biological Chemistry

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Aggregated and highly phosphorylated tau protein is a pathological hallmark of Alzheimer's disease (AD) and other tauopathies. We identified motifs of alternating polar and apolar amino acids within the microtubule-binding repeats of tau which were interrupted by small breaking stretches. Minimal mutation of these breaking sequences yielded a unique instantly aggregating tau mutant containing longer stretches of polar/ apolar amino acids without losing its microtubule-binding capacity. These modifications produced rapid aggregation and cytotoxicity with accompanying occurrence of pathologic tau phosphoepitopes (AT8, AT180, AT270, AT100, Ser 422 , and PHF-1) and conformational epitopes (MC-1 and Alz50) in cells. Similar to pathological tau in the pretangle state, toxicity appeared to occur early without the requirement for extensive fibril formation. Thus, our mutant protein provides a novel platform for the investigation of the molecular mechanisms for toxicity and cellular behavior of pathologically aggregated tau proteins and the identification of its interaction partners.Aggregates of hyperphosphorylated tau protein are a pathological hallmark of many neurodegenerative diseases, which include Alzheimer disease (AD), 3 frontotemporal dementia with Parkinson syndrome linked to chromosome 17 (FTDP-17), and others (1, 2). These aggregates can become entangled in the form of neurofibrillary tangles that are held responsible for neuronal cell death via yet unknown intracellular mechanisms.The tau protein exists as a naturally unfolded protein that is associated with microtubules. However, within pathological aggregates like neurofibrillary tangles, a ␤-strand conformation can be identified (3, 4). The physiological function of tau involves the binding and stabilization of the microtubule cytoskeleton. It exists as several splicing isoforms in the central nervous system. The expression levels of the different isoforms vary during the development and maturation of the central nervous system. This probably serves to modulate neuronal microtubule stability and function.The tau isoforms contain three or four C-terminal microtubule-binding repeats (MTBRs) and one or two acidic residues at the N terminus. The latter domains are not directly involved in the binding of microtubules, whereas the MTBRs of tau bind to the acidic C terminus of the tubulin monomers. The naturally unfolded nature of tau is probably explained by the fact that an extended conformation allows its interaction with several tubulin dimers (5).In the course of several diseases of the nervous system, tau molecules aggregate in the form of pathological multimers. Isolated tau protein exhibits a tendency to aggregate in the form of fibrils when incubated in the presence of polyanionic compounds or fatty acid-like molecules (3). It has been shown that the third MTBR contains a sequence that aggregates in isolated form (6), and accordingly, the MTBRs have been shown to be located in the core of fibrils by tryptophan fluorescence scanning spectroscopy (4). Ho...

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Conformation of paired helical filaments blocks dephosphorylation of epitopes shared with fetal tau except Ser199/202 and Ser202/Thr205

Cited by 34 publications

References 60 publications

Proline‐directed phosphorylation and isomerization in mitotic regulation and in Alzheimer's Disease

Proline‐directed phosphorylation and isomerization in mitotic regulation and in Alzheimer's Disease

Differential Changes in Phosphorylation of Tau at PHF-1 and 12E8 Epitopes During Brain Ischemia and Reperfusion in Gerbils

Removal of Pattern-breaking Sequences in Microtubule Binding Repeats Produces Instantaneous Tau Aggregation and Toxicity

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