In vitro polymerization of oxidized tau into filaments

Troncoso, Juan C.; Costello, Anthony C.; Watson, Arthur L.; Johnson, Gail V.W.

doi:10.1016/0006-8993(93)90918-d

Cited by 77 publications

(43 citation statements)

References 15 publications

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“…Tau isolated from Alzheimer disease brains no longer binds to microtubules; thus, microtubule stability in neurons is compromised. Sulfhydryl oxidation of tau has been suggested as a possible early step in the formation of paired helical filaments (16,17). For example, cysteine 322 in the microtubule-binding domain of human tau has been identified as a residue capable of forming disulfide cross-links (16).…”

Section: Reactions 1 Andmentioning

confidence: 99%

Cysteine Oxidation of Tau and Microtubule-associated Protein-2 by Peroxynitrite

Landino

Skreslet

Alston

2004

Journal of Biological Chemistry

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Alterations in the redox status of proteins have been implicated in the pathology of several neurodegenerative conditions including Alzheimer and Parkinson diseases. We report that peroxynitrite-and hydrogen peroxide-induced disulfides in the neuron-specific microtubule-associated proteins tau and microtubuleassociated protein-2 are substrates for the ubiquitous thioredoxin reductase system composed of thioredoxin reductase, human or Escherichia coli thioredoxin, and NADPH. Tau and microtubule-associated protein-2 cysteine oxidation and reduction were quantitated by monitoring the incorporation of 5-iodoacetamidofluorescein, a thiol-specific labeling reagent. Cysteine oxidation of tau and microtubule-associated protein-2 to disulfides altered the ability of the proteins to promote the assembly of microtubules from purified porcine tubulin. Treatment of tau and microtubule-associated protein-2 with either the thioredoxin reductase system or small molecule reductants fully restores the ability of the MAPs to promote microtubule assembly. Thus changes in the redox state of microtubule-associated proteins may regulate microtubule polymerization in vivo.Strong evidence implicates oxidative damage to proteins as well as cytoskeletal abnormalities in the pathogenesis of several neurodegenerative diseases including Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis (1, 2). Microtubules formed by reversible polymerization and depolymerization of tubulin, a heterodimer composed of similar 50 kDa ␣ and ␤ subunits, are key components of the neuronal cytoskeleton and are required for proper neuron function (3, 4). In addition to tubulin, the neuron-specific microtubule-associated proteins (MAPs), 1 MAP2 and tau, play a vital role in promoting and maintaining the neuronal cytoskeleton (5).Given the abundance of tubulin, tau, and MAP2 and the critical function they play in neurons, we are interested in studying the interaction they have with reactive oxygen species including peroxynitrite anion (ONOO Ϫ ) and hydrogen peroxide (H 2 O 2 ). ONOO Ϫ , formed from the reaction of nitric oxide and superoxide, is a strong oxidant that can damage several amino acids in proteins (6, 7).Previously we showed that tubulin, with 20 free sulfhydryl groups, is readily oxidized by ONOO Ϫ , and the extent of tubulin cysteine oxidation rather than other types of ONOO Ϫ -induced damage, correlates well with inhibition of microtubule polymerization (8). Addition of disulfide reducing agents restores a significant portion of the polymerization activity that is lost following ONOO Ϫ addition. Recently we reported (9, 10) that intra-and inter-subunit tubulin disulfides are substrates for two endogenous protein reductase systems including the thioredoxin reductase system (TRS) and the glutaredoxin reductase system.

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Section: Reactions 1 Andmentioning

confidence: 99%

Cysteine Oxidation of Tau and Microtubule-associated Protein-2 by Peroxynitrite

Landino

Skreslet

Alston

2004

Journal of Biological Chemistry

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“…7±12 Among the MCO systems, ascorbate/ Fe 3 treatment has been applied to study the correlation of oxidation processes with the presence of abnormal ®lamentous structures in Alzheimers disease. 13 Also, these systems have been used to analyse enzyme activity in red blood cells. 14 Diamide is a known oxidizing reagent whose effects could be related to the generation of senescent antigen by blocking of SH groups and which promote binding of autologous antibodies and phagocytosis.…”

Section: Introductionmentioning

confidence: 99%

Influence of oxidation and crosslinking on oxygen binding properties of mouse erythrocytes

Lotero

Jordán

López

et al. 2001

Cell Biochemistry & Function

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Different chemical treatments for mouse erythrocyte modification has been used. Oxidation treatments with Ascorbate/Fe(3+), a system able to react with intracellular proteins, produced a displacement of the O(2) binding equilibrium curve to a higher affinity behaviour with loss of the haemoglobin cooperativity for oxygen binding. Incubation of mouse erythrocytes with diamide showed that at low reagent concentration (0.8 mM) no modification on oxygen binding equilibrium curves was observed. At higher reagent concentration (2.0 mM), an increased affinity and a disappearance of the cooperative behaviour can be observed. Additionally, crosslinking reactions on mouse erythrocytes with band 3 crosslinkers seemed to affect oxygen binding properties when used at a crosslinker concentration of 5 mM. Oxyhaemoglobin levels in crosslinked and diamide-treated erythrocytes are similar to those found in control cells. In contrast, ascorbate/Fe(3+) treatments produced an increment in the proportion of methaemoglobin, decreasing the oxyhaemoglobin levels in these oxidized erythrocytes.

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“…The molecular mechanisms responsible for PHF assembly are poorly understood (13). Several studies have shown that tau protein can form polymers in vitro (14)(15)(16)(17)(18)(19)(20). A feature common to assembly-competent fragments is the presence of the tandem repeat region.…”

mentioning

confidence: 99%

Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines.

Wischik¹,

Edwards²,

Lai³

et al. 1996

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

501

437

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In Alzheimer disease (AD) the microtubuleassociated protein tau is redistributed exponentially into paired helical filaments (PHFs) forming neurofibrillary tangles, which correlate with pyramidal cell destruction and dementia. Amorphous neuronal deposits and PHFs in AD are characterized by aggregation through the repeat domain and C-terminal truncation at Glu-391 by endogenous proteases.We show that a similar proteolytically stable complex can be generated in vitro following the self-aggregation of tau protein through a high-affinity binding site in the repeat domain. Once started, tau capture can be propagated by seeding the further accumulation of truncated tau in the presence of proteases. We have identified a nonneuroleptic phenothiazine previously used in man (methylene blue, MB), which reverses the proteolytic stability of protease-resistant PHFs by blocking the tau-tau binding interaction through the repeat domain. Although MB is inhibitory at a higher concentration than may be achieved clinically, the tau-tau binding assay was used to identify desmethyl derivatives of MB that have K; values in the nanomolar range. Neuroleptic phenothiazines are inactive. Tau aggregation inhibitors do not affect the tau-tubulin interaction, which also occurs through the repeat domain. Our findings demonstrate that biologically selective pharmaceutical agents could be developed to facilitate the proteolytic degradation of tau aggregates and prevent the further propagation of tau capture in AD.

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In vitro polymerization of oxidized tau into filaments

Cited by 77 publications

References 15 publications

Cysteine Oxidation of Tau and Microtubule-associated Protein-2 by Peroxynitrite

Cysteine Oxidation of Tau and Microtubule-associated Protein-2 by Peroxynitrite

Influence of oxidation and crosslinking on oxygen binding properties of mouse erythrocytes

Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines.

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