scholarly journals Ferroptosis Promotes Microtubule-Associated Protein Tau Aggregation via GSK-3β Activition and Proteasome Inhibition

2021 ◽  
Author(s):  
Shaohui Wang ◽  
Yao Jiang ◽  
Yabo Liu ◽  
Qianhui Liu ◽  
Hongwei Sun ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Neuroblastoma Cells ◽  
Proteasome Inhibition ◽  
Brain Regions ◽  
Protein Tau ◽  
Microtubule Associated Protein Tau ◽  
Regulated Cell Death ◽  
Wide Range ◽  
Gsk 3Β ◽  
Tau Aggregation

Abstract Ferroptosis is a form of regulated cell death resulting from iron accumulation and lipid peroxidation. In some particular brain regions, iron dyshomeostasis and peroxidation damage of neurons are closely related to a wide range of neurodegenerative diseases known as “tauopathies”, in which intracellular aggregation of microtubule-associated protein tau is the common neuropathological feature. However, the relationship between ferroptosis and tau aggregation is not well understood. The current study demonstrates that erastin-induced ferroptosis can promote tau hyperphosphorylation and aggregation in mouse neuroblastoma cells (N2a cells). Moreover, ferroptosis inhibitor ferrostatin-1 can alleviate tau aggregation effectively. In-depth mechanism research indicates that activated Glycogen synthase kinase-3β (GSK-3β) is responsible for abnormal hyperphosphorylation and accumulation. More importantly, proteasome inhibition can exacerbate the tau degradation obstacle and accelerate tau aggregation in the process of ferroptosis. Our results indicate that ferroptosis can lead to abnormal aggregation of tau protein and might be a promising therapeutic target of tauopathies.

scholarly journals The kinase DYRK phosphorylates protein-synthesis initiation factor eIF2Bɛ at Ser539 and the microtubule-associated protein tau at Thr212: potential role for DYRK as a glycogen synthase kinase 3-priming kinase

2001 ◽  
Vol 355 (3) ◽  
pp. 609-615 ◽  
Author(s):  
Yvonne L. WOODS ◽  
Philip COHEN ◽  
Walter BECKER ◽  
Ross JAKES ◽  
Michel GOEDERT ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Protein Kinases ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Initiation Factor ◽  
Glycogen Synthase Kinase 3 ◽  
General Role ◽  
Protein Tau ◽  
Microtubule Associated Protein Tau ◽  
Protein Synthesis Initiation

The substrate specificity of glycogen synthase kinase 3 (GSK3) is unusual in that efficient phosphorylation only occurs if another phosphoserine or phosphothreonine residue is already present four residues C-terminal to the site of GSK3 phosphorylation. One such substrate is the ε-subunit of rat eukaryotic protein-synthesis initiation factor 2B (eIF2Bε), which is inhibited by the GSK3-catalysed phosphorylation of Ser535. There is evidence that GSK3 is only able to phosphorylate eIF2Bε at Ser535 if Ser539 is already phosphorylated by another protein kinase. However, no protein kinases capable of phosphorylating Ser539 have so far been identified. Here we show that Ser539 of eIF2Bε, which is followed by proline, is phosphorylated specifically by two isoforms of dual-specificity tyrosine phosphorylated and regulated kinase (DYRK2 and DYRK1A), but only weakly or not at all by other ‘proline-directed’ protein kinases tested. We also establish that phosphorylation of Ser539 permits GSK3 to phosphorylate Ser535in vitro and that eIF2Bε is highly phosphorylated at Ser539in vivo. The DYRK isoforms also phosphorylate human microtubule-associated protein tau at Thr212in vitro, a residue that is phosphorylated in foetal tau and hyperphosphorylated in filamentous tau from Alzheimer's-disease brain. Phosphorylation of Thr212 primes tau for phosphorylation by GSK3 at Ser208in vitro, suggesting a more general role for DYRK isoforms in priming phosphorylation of GSK3 substrates.

scholarly journals Glycogen synthase kinase-3 and the Alzheimer-like state of microtubule-associated protein tau

FEBS Letters ◽  
1992 ◽  
Vol 314 (3) ◽  
pp. 315-321 ◽  
Author(s):  
E.-M. Mandelkow ◽  
G. Drewes ◽  
J. Biernat ◽  
N. Gustke ◽  
J. Van Lint ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Protein Tau ◽  
Microtubule Associated Protein Tau

scholarly journals Dishevelled-1 Regulates Microtubule Stability

2000 ◽  
Vol 151 (1) ◽  
pp. 83-94 ◽  
Author(s):  
Olga Krylova ◽  
Marcus J. Messenger ◽  
Patricia C. Salinas
Keyword(s):  
Cell Fate ◽  
Cell Polarity ◽  
Cellular Localization ◽  
Glycogen Synthase ◽  
Pdz Domain ◽  
Neuroblastoma Cells ◽  
Cell Fate Decisions ◽  
Microtubule Stabilization ◽  
Microtubule Stability ◽  
Gsk 3Β

Dishevelled has been implicated in the regulation of cell fate decisions, cell polarity, and neuronal function. However, the mechanism of Dishevelled action remains poorly understood. Here we examine the cellular localization and function of the mouse Dishevelled protein, DVL-1. Endogenous DVL-1 colocalizes with axonal microtubules and sediments with brain microtubules. Expression of DVL-1 protects stable microtubules from depolymerization by nocodazole in both dividing cells and differentiated neuroblastoma cells. Deletion analyses reveal that the PDZ domain, but not the DEP domain, of DVL-1 is required for microtubule stabilization. The microtubule stabilizing function of DVL-1 is mimicked by lithium-mediated inhibition of glycogen synthase kinase-3β (GSK-3β) and blocked by expression of GSK-3β. These findings suggest that DVL-1, through GSK-3β, can regulate microtubule dynamics. This new function of DVL-1 in controlling microtubule stability may have important implications for Dishevelled proteins in regulating cell polarity.

scholarly journals Glycogen Synthase Kinase-3 Regulates Production of Amyloid-βPeptides and Tau Phosphorylation in Diabetic Rat Brain

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Zhong-Sen Qu ◽  
Liang Li ◽  
Xiao-Jiang Sun ◽  
Yu-Wu Zhao ◽  
Jin Zhang ◽  
...  
Keyword(s):  
Rat Brain ◽  
Glycogen Synthase ◽  
Selective Inhibition ◽  
Neurological Complications ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Diabetic Rat ◽  
Protein Tau ◽  
Microtubule Associated Protein Tau ◽  
Amyloid Deposits

The pathogenesis of diabetic neurological complications is not fully understood. Diabetes mellitus (DM) and Alzheimer’s disease (AD) are characterized by amyloid deposits. Glycogen synthase kinase-3 (GSK-3) plays an important role in the pathogenesis of AD and DM. Here we tried to investigate the production of amyloid-βpeptides (Aβ) and phosphorylation of microtubule-associated protein tau in DM rats and elucidate the role of GSK-3 and Akt (protein kinase B, PKB) in these processes. Streptozotocin injection-induced DM rats displayed an increased GSK-3 activity, decreased activity and expression of Akt. And Aβ40 and Aβ42 were found overproduced and the microtubule-associated protein tau was hyperphosphorylated in the hippocampus. Furthermore, selective inhibition of GSK-3 by lithium could attenuate the conditions of Aβoverproduction and tau hyperphosphorylation. Taken together, our studies suggest that GSK-3 regulates both the production of Aβand the phosphorylation of tau in rat brain and may therefore contribute to DM caused AD-like neurological defects.

scholarly journals The Role of GSK-3β in the Regulation of Protein Turnover, Myosin Phenotype, and Oxidative Capacity in Skeletal Muscle under Disuse Conditions

2021 ◽  
Vol 22 (10) ◽  
pp. 5081
Author(s):  
Timur M. Mirzoev ◽  
Kristina A. Sharlo ◽  
Boris S. Shenkman
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Protein Turnover ◽  
Skeletal Muscles ◽  
Glycogen Synthase ◽  
Oxidative Capacity ◽  
The Body ◽  
Vital Functions ◽  
Wide Range ◽  
Gsk 3Β

Skeletal muscles, being one of the most abundant tissues in the body, are involved in many vital processes, such as locomotion, posture maintenance, respiration, glucose homeostasis, etc. Hence, the maintenance of skeletal muscle mass is crucial for overall health, prevention of various diseases, and contributes to an individual’s quality of life. Prolonged muscle inactivity/disuse (due to limb immobilization, mechanical ventilation, bedrest, spaceflight) represents one of the typical causes, leading to the loss of muscle mass and function. This disuse-induced muscle loss primarily results from repressed protein synthesis and increased proteolysis. Further, prolonged disuse results in slow-to-fast fiber-type transition, mitochondrial dysfunction and reduced oxidative capacity. Glycogen synthase kinase 3β (GSK-3β) is a key enzyme standing at the crossroads of various signaling pathways regulating a wide range of cellular processes. This review discusses various important roles of GSK-3β in the regulation of protein turnover, myosin phenotype, and oxidative capacity in skeletal muscles under disuse/unloading conditions and subsequent recovery. According to its vital functions, GSK-3β may represent a perspective therapeutic target in the treatment of muscle wasting induced by chronic disuse, aging, and a number of diseases.

scholarly journals Microtubule-associated protein tau is essential for long-term depression in the hippocampus

2014 ◽  
Vol 369 (1633) ◽  
pp. 20130144 ◽  
Author(s):  
Tetsuya Kimura ◽  
Daniel J. Whitcomb ◽  
Jihoon Jo ◽  
Philip Regan ◽  
Thomas Piers ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Principal Component ◽  
Synaptic Function ◽  
Glycogen Synthase Kinase 3 ◽  
Long Term Depression ◽  
Protein Tau ◽  
Microtubule Associated Protein Tau

The microtubule-associated protein tau is a principal component of neurofibrillary tangles, and has been identified as a key molecule in Alzheimer's disease and other tauopathies. However, it is unknown how a protein that is primarily located in axons is involved in a disease that is believed to have a synaptic origin. To investigate a possible synaptic function of tau, we studied synaptic plasticity in the hippocampus and found a selective deficit in long-term depression (LTD) in tau knockout mice in vivo and in vitro , an effect that was replicated by RNAi knockdown of tau in vitro . We found that the induction of LTD is associated with the glycogen synthase kinase-3-mediated phosphorylation of tau. These observations demonstrate that tau has a critical physiological function in LTD.

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