Amyloid β induces neuronal cell death through ROS-mediated ASK1 activation

Kadowaki, Hisae; Nishitoh, Hideki; Urano, Fumihiko; Sadamitsu, Chiharu; Matsuzawa, Atsushi; Takeda, Kohsuke; Masutani, Hiroshi; Yodoi, Junji; Urano, Yasuteru; Nagano, Tetsuo; Ichijo, Hidenori

doi:10.1038/sj.cdd.4401528

Cited by 375 publications

(333 citation statements)

References 33 publications

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“…Ask1 plays an important role in the cell response to oxidative stress, being essential for the activation of the stressactivated protein kinase JNK (Gotoh and Cooper, 1998;Tobiume et al, 2001;Machino et al, 2003;Saadatzadeh et al, 2004;Kadowaki et al, 2005). As expected, exposure of HEK293 cells to H 2 O 2 induced the rapid phosphorylation of JNK ( Figure 1E), which was increased severalfold by pretransfecting the cells with a HA-tagged version of Ask1 (Ask1-HA) ( Figure 1A, lanes 3 and 4).…”

Section: In Vivo Oxidation Of Ask1 By H 2 Osupporting

confidence: 62%

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Disulfide Bond-mediated Multimerization of Ask1 and Its Reduction by Thioredoxin-1 Regulate H₂O₂-induced c-Jun NH₂-terminal Kinase Activation and Apoptosis

Nadeau

Charette

Toledano

et al. 2007

MBoC

171

137

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Apoptosis signal-regulated kinase-1 (Ask1) lies upstream of a major redox-sensitive pathway leading to the activation of Jun NH 2 -terminal kinase (JNK) and the induction of apoptosis. We found that cell exposure to H 2 O 2 caused the rapid oxidation of Ask1, leading to its multimerization through the formation of interchain disulfide bonds. Oxidized Ask1 was fully reduced within minutes after induction by H 2 O 2 . During this reduction, the thiol-disulfide oxidoreductase thioredoxin-1 (Trx1) became covalently associated with Ask1. Overexpression of Trx1 accelerated the reduction of Ask1, and a redox-inactive mutant of Trx1 (C35S) remained trapped with Ask1, blocking its reduction. Preventing the oxidation of Ask1 by either overexpressing Trx1 or using an Ask1 mutant in which the sensitive cysteines were mutated (Ask1-⌬Cys) impaired the activation of JNK and the induction of apoptosis while having little effect on Ask1 activation. These results indicate that Ask1 oxidation is required at a step subsequent to activation for signaling downstream of Ask1 after H 2 O 2 treatment. INTRODUCTIONH 2 O 2 is emerging as an important intracellular signaling molecule affecting a variety of cellular responses. In mammals, H 2 O 2 concentration transiently increases in response to different membrane-receptor agonists such as peptide growth factors, hormones, cytokines, and neurotransmitters. This increase of H 2 O 2 concentration is important for downstream signaling from the corresponding membrane receptors (Deyulia et al., 2005;Rhee et al., 2005;Stone and Yang, 2006). Some of these H 2 O 2 regulatory effects are mediated by protein-thiol oxidation, as shown for the oxidative inhibition of protein tyrosine phosphatase upon receptor-tyrosine kinases engagement. H 2 O 2 can oxidize cysteine residues to the sulfenic (protein-SOH), sulfinic (protein-SO 2 H), and sulfonic acid (protein-SO 3 H) forms, also leading to intra-or intermolecular disulfide bonds (protein-SS-protein) and to protein glutathionylation (protein-SSG). Similarly to protein posttranslational modification by serine, threonine, and tyrosine phosphorylation, oxidation of cysteine residues can trigger changes in protein conformation and activity (Filomeni et al., 2005). In bacteria, OxyR is an archetypical H 2 O 2 sensor at the top of a redox-sensitive pathway, being activated by H 2 O 2 through formation of an intramolecular disulfide bond and controlling the transcription of antioxidant defense genes (Storz and Tartaglia, 1992;Zheng et al., 1998). In yeast, H 2 O 2 sensing involves the thiol-based peroxidase Orp1/Gpx3, which, upon oxidation by H 2 O 2 , mediates the formation of an intramolecular disulfide bond in the Yap1 transcription factor, causing its activation (Lee et al., 1999;Delaunay et al., 2002).The mitogen-activated protein kinase kinase kinase apoptosis signal-regulated kinase-1 (Ask1) and its downstream stress-activated kinases p38 and Jun NH 2 -terminal kinase (JNK) constitute an important mammalian signaling pathway that can promote cell surviv...

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Section: In Vivo Oxidation Of Ask1 By H 2 Osupporting

confidence: 62%

“…Ask1 can be activated by H 2 O 2 ; thus, it is part of a redox-signaling pathway (Gotoh and Cooper, 1998;Tobiume et al, 2001;Kadowaki et al, 2005;Noguchi et al, 2005). The activation of Ask1 by H 2 O 2 is regulated by the disulfide reductase thioredoxin-1 (Trx1).…”

Section: Introductionmentioning

confidence: 99%

Disulfide Bond-mediated Multimerization of Ask1 and Its Reduction by Thioredoxin-1 Regulate H₂O₂-induced c-Jun NH₂-terminal Kinase Activation and Apoptosis

Nadeau

Charette

Toledano

et al. 2007

MBoC

171

137

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“…Similar results have also been reported for amyloid-ß aggregation reactions, supporting the observations with aggregation-prone HTTex1 fragments [28]. Intriguingly, experimental evidence suggests that aggregates formed of simple polyQ peptides are cytotoxic for mammalian cells when transported into the nucleus [29].…”

Section: Proteotoxicity Of Polyq-containing Protein Aggregatessupporting

confidence: 84%

Spontaneous self-assembly of pathogenic huntingtin exon 1 protein into amyloid structures

Trepte

Strempel

Wanker

2014

Essays in Biochemistry

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Published in final edited form as:Trepte, P., Strempel, N., Wanker, E.E. Spontaneous self-assembly of pathogenic huntingtin exon 1 protein into amyloid structures. Abstract:Polyglutamine ( This chapter reviews the current literature regarding misfolding and aggregation of polyQ-containing disease proteins. We specifically focus on studies that have investigated the amyloidogenesis of polyQ-containing huntingtin exon 1 (HTTex1) fragments. These protein fragments are disease-relevant and play a critical role in HD pathogenesis. We will outline potential mechanisms behind mutant HTTex1 aggregation and toxicity, as well as proteins and small molecules that can modify HTTex1 amyloidogenesis in vitro and in vivo. The potential implications of such studies for the development of novel therapeutic strategies are discussed.

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“…39 Fibrillar Ab is toxic to neuronal cells and produces high amounts of ROS with the impairment of the mitochondrial redox activity. 39,40 Recent studies have shown an involvement of ER stress and disturbed calcium homeostasis in AD. 11,39,41 Analyses of brain tissue from AD patients revealed alterations in calcium metabolism that are associated with the neurodegenerative process.…”

Section: Er Stress and Admentioning

confidence: 99%

ER stress and neurodegenerative diseases

2006

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Amyloid β induces neuronal cell death through ROS-mediated ASK1 activation

Cited by 375 publications

References 33 publications

Disulfide Bond-mediated Multimerization of Ask1 and Its Reduction by Thioredoxin-1 Regulate H₂O₂-induced c-Jun NH₂-terminal Kinase Activation and Apoptosis

Disulfide Bond-mediated Multimerization of Ask1 and Its Reduction by Thioredoxin-1 Regulate H₂O₂-induced c-Jun NH₂-terminal Kinase Activation and Apoptosis

Spontaneous self-assembly of pathogenic huntingtin exon 1 protein into amyloid structures

ER stress and neurodegenerative diseases

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Amyloid β induces neuronal cell death through ROS-mediated ASK1 activation

Cited by 375 publications

References 33 publications

Disulfide Bond-mediated Multimerization of Ask1 and Its Reduction by Thioredoxin-1 Regulate H2O2-induced c-Jun NH2-terminal Kinase Activation and Apoptosis

Disulfide Bond-mediated Multimerization of Ask1 and Its Reduction by Thioredoxin-1 Regulate H2O2-induced c-Jun NH2-terminal Kinase Activation and Apoptosis

Spontaneous self-assembly of pathogenic huntingtin exon 1 protein into amyloid structures

ER stress and neurodegenerative diseases

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Disulfide Bond-mediated Multimerization of Ask1 and Its Reduction by Thioredoxin-1 Regulate H₂O₂-induced c-Jun NH₂-terminal Kinase Activation and Apoptosis

Disulfide Bond-mediated Multimerization of Ask1 and Its Reduction by Thioredoxin-1 Regulate H₂O₂-induced c-Jun NH₂-terminal Kinase Activation and Apoptosis