Energy determinants GAPDH and NDPK act as genetic modifiers for hepatocyte inclusion formation

Snider, Natasha T.; Weerasinghe, Sujith; Singla, Anuj; Leonard, Jessica M.; Hanada, Shinichiro; Andrews, Philip C.; Lok, Anna S.; Omary, M. Bishr

doi:10.1083/jcb.201102142

Cited by 33 publications

(46 citation statements)

References 59 publications

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“…These models of GAPDH aggregation are supported by the observation that insoluble disulfide-cross-linked forms of GAPDH have been found in vivo (11)(12)(13)18). Our data suggest that cysteine oxidation contributes to GAPDH aggregation; however, we found that oxidation of non-cysteine residues has a more influential and primary role in GAPDH aggregation.…”

Section: Discussionsupporting

confidence: 54%

“…For instance, insoluble aggregates of GAPDH have been observed in the affected tissues of patients with Alzheimer disease (13) and alcoholic liver cirrhosis (12). Interestingly, GAPDH is also a susceptibility locus for late onset Alzheimer disease (21).…”

mentioning

confidence: 99%

“…Indeed, GAPDH aggregates formed in vivo (11)(12)(13)18) and in vitro (10,11,18,22,23) have been shown to be disulfide-cross-linked. Recently, we discovered another instance where GAPDH converts into an insoluble disulfide-cross-linked state (18).…”

mentioning

confidence: 99%

“…In vivo studies show that GAPDH converts from its native soluble state into a non-native high molecular weight insoluble state during disease (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). For instance, insoluble aggregates of GAPDH have been observed in the affected tissues of patients with Alzheimer disease (13) and alcoholic liver cirrhosis (12).…”

mentioning

confidence: 99%

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Oxidation of an Exposed Methionine Instigates the Aggregation of Glyceraldehyde-3-phosphate Dehydrogenase

Samson

Knaupp

Kass

et al. 2014

Journal of Biological Chemistry

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Background: GAPDH is a glycolytic enzyme that aggregates during disease. Cysteine oxidation is the putative cause of aggregation. Whether GAPDH aggregation influences disease is unknown. Results: Mutating Met-46 renders GAPDH resistant to free radical-induced aggregation. Conclusion: Methionine oxidation, rather than cysteine oxidation, is a primary event that instigates GAPDH aggregation. Significance: Mutating Met-46 in vivo should elucidate whether GAPDH aggregation causally contributes to disease.

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Section: Discussionsupporting

confidence: 54%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Oxidation of an Exposed Methionine Instigates the Aggregation of Glyceraldehyde-3-phosphate Dehydrogenase

Samson

Knaupp

Kass

et al. 2014

Journal of Biological Chemistry

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“…To determine if ␤-catenin knockdown exacerbates oxidative injury in vivo, we subjected KD mice and littermates to a DDC-containing diet for 3 weeks. DDC is a porphyrinogenic agent that causes chronic oxidative liver damage and Mallory-Denk body formations (39). Effective ␤-catenin deletion in response to doxycycline withdrawal for 4 weeks was confirmed by mRNA and protein analysis ( Fig.…”

Section: ␤-Catenin Signaling Provides Hepatocyte Protection Against Omentioning

confidence: 98%

Wnt/β-Catenin Signaling Protects Mouse Liver against Oxidative Stress-induced Apoptosis through the Inhibition of Forkhead Transcription Factor FoxO3

Guo

Lehwald

Jang

et al. 2013

Journal of Biological Chemistry

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114

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Background: Wnt/␤-catenin signaling regulates various hepatocellular processes; however, it remains unexplored whether ␤-catenin provides hepatocyte protection against oxidative stress-induced apoptosis. Results: Mice with ␤-catenin-deficient hepatocytes demonstrate significantly increased hepatotoxin-induced liver injury. Conclusion: Hepatic ␤-catenin signaling confers hepatocyte protection against oxidative stress-induced apoptosis. Significance: Our findings have relevance for potential future therapies directed at hepatocyte protection, regeneration, and anti-cancer treatment.

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Broad Spectrum of Hepatocyte Inclusions in Humans, Animals, and Experimental Models

Strnad

Nuraldeen

Güldiken

et al. 2013

Comprehensive Physiology

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We focus on hepatic inclusions, which are defined as intracellular aggregates of stainable substances. They represent established hallmarks of their respective human disorders, but unlike aggregates found in neurodegenerative disorders are often not well studied. Hepatic inclusions can be subdivided into primary liver aggregates and aggregates found in multiple tissues. The former ones consist of inclusions found in endoplasmic reticulum storage diseases such as α 1-antitrypsin aggregates or ground-glass hepatocytes, p62-containing (Mallory-Denk bodies and intracellular hyaline bodies) and porphyrin-containing inclusions. p62-containing aggregates are not restricted to the liver but are found in multiple other disorders such as Parkinson or Alzheimer disease. Inclusions such as pale bodies or intracellular hyaline bodies are typical for malignant disorders while others (ground-glass hepatocytes and α1-antitrypsin aggregates) are predominantly seen in non-neoplastic tissues. The inclusions, which are not restricted to the liver, are often due to a systemic viral infection, but also due to disruption of glycogen metabolism or systemic inclusion-forming diseases such as polyglutamine disorders or sarcoidosis. Despite their heterogeneity, inclusions share several pathogenic principles such as an imbalance between protein damage/misfolding on one side and repair/degradation on the other side. This is why hepatic aggregates represent a valuable tool to study the aggregation process in general and to improve our understanding of inclusions found in multiple human disorders.

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Energy determinants GAPDH and NDPK act as genetic modifiers for hepatocyte inclusion formation

Abstract: Differential expression and activity of the cellular energy regulators GAPDH and NDPK underlie reactive oxygen species–induced damage in the mouse liver and may contribute to human liver disease progression.

Cited by 33 publications

References 59 publications

Oxidation of an Exposed Methionine Instigates the Aggregation of Glyceraldehyde-3-phosphate Dehydrogenase

Oxidation of an Exposed Methionine Instigates the Aggregation of Glyceraldehyde-3-phosphate Dehydrogenase

Wnt/β-Catenin Signaling Protects Mouse Liver against Oxidative Stress-induced Apoptosis through the Inhibition of Forkhead Transcription Factor FoxO3

Broad Spectrum of Hepatocyte Inclusions in Humans, Animals, and Experimental Models

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