Structural insights into Alzheimer filament assembly pathways based on site‐directed mutagenesis and <i>S</i>‐glutathionylation of three‐repeat neuronal Tau protein

DiNoto, L.; DeTure, Michael; Purich, Daniel L.

doi:10.1002/jemt.20195

Cited by 26 publications

(18 citation statements)

References 65 publications

(64 reference statements)

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“…S -glutathionylated actin was reported in AD brain by Dalle-Donne et al (50). Other proteins such as GAPDH, hemoglobin, crystalline B, α enolase also shown to be thiolated, causing a disturbance in glucose metabolism and oxygen supply in neurons (12, 51). In the present study, alteration in redox status along with enhanced LPO observed in the blood of AD patients might also contribute to thiolation of crucial blood proteins.…”

Section: Discussionmentioning

confidence: 99%

Study on Analysis of Peripheral Biomarkers for Alzheimer’s Disease Diagnosis

2017

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Many factors are involved in Alzheimer’s disease (AD) pathology including tau phosphorylation, amyloid β protein (Aβ) accumulation, lipid dysregulation, oxidative stress, and inflammation. The markers of these pathological processes in cerebral spinal fluid are used currently for AD diagnosis. However, peripheral biomarkers are the need of the hour for large population screening for AD. The main objective of the present study is to evaluate the peripheral levels of redox markers, lipid peroxidation (LPO) indicators, and pathological markers in AD patients. Blood was collected from AD patients (n = 45), controls (n = 45), and analyzed for pathological markers of AD including Aβ42 and tau, LPO, and redox indicators. Plasma Aβ42 was significantly (P < 0.001) elevated while total tau was decreased in AD compared to controls. Hydroxynonenal (HNE) and malondialdehyde (MDA) were higher (P < 0.001) in AD patients pointing the enhanced LPO in AD pathology. Receiver operating characteristic curve (ROC) analysis indicated that HNE is a better indicator of LPO compared to MDA. Plasma glutathione (GSH) level was significantly (P < 0.001) low while oxidized glutathione (GSSG) level was higher (P < 0.001) in AD patients with corresponding decrease in GSH/GSSG ratio (P < 0.001). ROC analysis indicated that GSH/GSSG ratio can be used as reliable indicator for redox imbalance in AD with a cutoff value of <8.73 (sensitivity 91.1%, specificity 97.8%). Correlation analysis revealed a positive correlation for both HNE and MDA with Aβ42 and a negative correlation with total tau. Negative correlation was observed between GSH/GSSG ratio and LPO markers. While oxidative stress has been implicated in pathology of various neurodegenerative disorders, the present study pinpoints the direct link between LPO and Aβ production in plasma of AD patients. Normally, at low amyloid concentration in body fluids, this peptide shown to function as a strong metal chelating antioxidant. However, when the Aβ production enhanced as in AD, through gain of functional transformation, Aβ evolves into prooxidant, thereby enhancing oxidative stress and LPO. Altered redox status with enhanced LPO observed in AD blood could contribute to the oxidation and S-glutathionylation proteins, which has to be addressed in future studies.

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Section: Discussionmentioning

confidence: 99%

Study on Analysis of Peripheral Biomarkers for Alzheimer’s Disease Diagnosis

2017

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“…When Grx1 was knocked down by antisense oligonucleotides, inactivation of Complex I by MPTP was not observed. It is also interesting to note that glutathionylation of the tau protein causes it to polymerize and form the neurofibrillary tangles [194] found in AD.…”

Section: Deregulation Of Mitochondrial Thiol Reactions In Diseasementioning

confidence: 99%

Redox regulation of mitochondrial function with emphasis on cysteine oxidation reactions

2014

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Mitochondria have a myriad of essential functions including metabolism and apoptosis. These chief functions are reliant on electron transfer reactions and the production of ATP and reactive oxygen species (ROS). The production of ATP and ROS are intimately linked to the electron transport chain (ETC). Electrons from nutrients are passed through the ETC via a series of acceptor and donor molecules to the terminal electron acceptor molecular oxygen (O2) which ultimately drives the synthesis of ATP. Electron transfer through the respiratory chain and nutrient oxidation also produces ROS. At high enough concentrations ROS can activate mitochondrial apoptotic machinery which ultimately leads to cell death. However, if maintained at low enough concentrations ROS can serve as important signaling molecules. Various regulatory mechanisms converge upon mitochondria to modulate ATP synthesis and ROS production. Given that mitochondrial function depends on redox reactions, it is important to consider how redox signals modulate mitochondrial processes. Here, we provide the first comprehensive review on how redox signals mediated through cysteine oxidation, namely S-oxidation (sulfenylation, sulfinylation), S-glutathionylation, and S-nitrosylation, regulate key mitochondrial functions including nutrient oxidation, oxidative phosphorylation, ROS production, mitochondrial permeability transition (MPT), apoptosis, and mitochondrial fission and fusion. We also consider the chemistry behind these reactions and how they are modulated in mitochondria. In addition, we also discuss emerging knowledge on disorders and disease states that are associated with deregulated redox signaling in mitochondria and how mitochondria-targeted medicines can be utilized to restore mitochondrial redox signaling.

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“…Tau has a required cysteine residue (Cys 322) which facilitates its binding to microtubules. Cys322 has been reported to be oxidized in vitro, altering tau's ability to form dimers (45,46). In particular, polymerization of the Sglutathionylated form of three-repeat tau was interpreted as evidence that tau-S-S-tau dimer formation is not required for filament assembly (36).…”

Section: B Taumentioning

confidence: 99%

Mechanisms of Altered Redox Regulation in Neurodegenerative Diseases—Focus on S-Glutathionylation

Liedhegner

Gao

Mieyal

2012

Antioxidants & Redox Signaling

107

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Significance: Neurodegenerative diseases are characterized by progressive loss of neurons. A common feature is oxidative stress, which arises when reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) exceed amounts required for normal redox signaling. An imbalance in ROS/RNS alters functionality of cysteines and perturbs thiol-disulfide homeostasis. Many cysteine modifications may occur, but reversible protein mixed disulfides with glutathione (GSH) likely represents the common steady-state derivative due to cellular abundance of GSH and ready conversion of cysteine-sulfenic acid and S-nitrosocysteine precursors to S-glutathionylcysteine disulfides. Thus, S-glutathionylation acts in redox signal transduction and serves as a protective mechanism against irreversible cysteine oxidation. Reversal of protein-S-glutathionylation is catalyzed specifically by glutaredoxin which thereby plays a critical role in cellular regulation. This review highlights the role of oxidative modification of proteins, notably S-glutathionylation, and alterations in thiol homeostatic enzyme activities in neurodegenerative diseases, providing insights for therapeutic intervention. Recent Advances: Recent studies show that dysregulation of redox signaling and sulfhydryl homeostasis likely contributes to onset/progression of neurodegeneration. Oxidative stress alters the thiol-disulfide status of key proteins that regulate the balance between cell survival and cell death. Critical Issues: Much of the current information about redox modification of key enzymes and signaling intermediates has been gleaned from studies focused on oxidative stress situations other than the neurodegenerative diseases. Future Directions: The findings in other contexts are expected to apply to understanding neurodegenerative mechanisms. Identification of selectively glutathionylated proteins in a quantitative fashion will provide new insights about neuropathological consequences of this oxidative protein modification. Antioxid. Redox Signal. 16, 543-566.

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Structural insights into Alzheimer filament assembly pathways based on site‐directed mutagenesis and S‐glutathionylation of three‐repeat neuronal Tau protein

Cited by 26 publications

References 65 publications

Study on Analysis of Peripheral Biomarkers for Alzheimer’s Disease Diagnosis

Study on Analysis of Peripheral Biomarkers for Alzheimer’s Disease Diagnosis

Redox regulation of mitochondrial function with emphasis on cysteine oxidation reactions

Mechanisms of Altered Redox Regulation in Neurodegenerative Diseases—Focus on S-Glutathionylation

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