Association of NRH:Quinone Oxidoreductase 2 Gene Promoter Polymorphism With Higher Gene Expression and Increased Susceptibility to Parkinson's Disease

Wang, Wei; Le, Wei Dong; Pan, Tianhong; Stringer, Janet L.; Jaiswal, Anil K.

doi:10.1093/gerona/63.2.127

Cited by 37 publications

(27 citation statements)

References 33 publications

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“…It is noteworthy that human NQO2 gene promoter polymorphism is known to lead to lower expression of NQO2 in a significant portion of the population (19,20).…”

Section: Discussionmentioning

confidence: 99%

NRH:Quinone Oxidoreductase 2 (NQO2) Protein Competes with the 20 S Proteasome to Stabilize Transcription Factor CCAAT Enhancer-binding Protein α (C/EBPα), Leading to Protection against γ Radiation-induced Myeloproliferative Disease

Patrick

Jaiswal

2013

Journal of Biological Chemistry

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Background: NQO2 protects against ␥ radiation-induced myeloproliferative disease, but the mechanism remains unknown. Results: Radiation-induced NQO2, independent of NQO1, competes with the 20 S proteasome for interaction with C/EBP␣ region Ser-268 to Val-279 to stabilize C/EBP␣, leading to protection against myeloproliferative disease. Conclusion: NQO2 stabilizes C/EBP␣ against 20 S degradation to protect against myeloproliferative disease. Significance: Stress-responsive NQO2 functions as an endogenous factor against myeloproliferative diseases.

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“…It is noteworthy that human NQO2 gene promoter polymorphism is known to lead to lower expression of NQO2 in a significant portion of the population (19,20).…”

Section: Discussionmentioning

confidence: 99%

NRH:Quinone Oxidoreductase 2 (NQO2) Protein Competes with the 20 S Proteasome to Stabilize Transcription Factor CCAAT Enhancer-binding Protein α (C/EBPα), Leading to Protection against γ Radiation-induced Myeloproliferative Disease

Patrick

Jaiswal

2013

Journal of Biological Chemistry

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“…This has been enforced by in vivo experiments in which the coinjection of NRH with menadione in QR2 Ϫ/Ϫ mice led greater toxicity of the quinone (Long et al, 2002). It has been shown in neurodegenerative diseases that QR2 is overexpressed, suggesting that enhanced activity of QR2 could lead to neuronal cell death (Harada et al, 2001;Wang et al, 2008). This is likely attributable to two independent factors, namely the induction of the protein and the availability of NRH.…”

Section: Discussionmentioning

confidence: 99%

“…It was shown recently that the human QR2 promoter contains a binding site for the transcription factor Sp3 that represses QR2 gene transcription (Wang and Jaiswal, 2004). Moreover, a polymorphism in that region of the promoter has been suggested as a relatively weak susceptibility factor in the etiology of schizophrenia , Parkinson's disease (Harada et al, 2001;Wang et al, 2008), and other related mental disorders (Okubo et al, 2003;Ohgake et al, 2005). Accordingly, the major objective of the present study was first to demonstrate its expression and distribution in discrete mammalian brain.…”

Section: Introductionmentioning

confidence: 89%

Loss of Quinone Reductase 2 Function Selectively Facilitates Learning Behaviors

Benoit¹,

Bastianetto²,

Brouillette³

et al. 2010

J. Neurosci.

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High levels of reactive oxygen species (ROS) are associated with deficits in learning and memory with age as well as in Alzheimer's disease. Using DNA microarray, we demonstrated the overexpression of quinone reductase 2 (QR2) in the hippocampus in two models of learning deficits, namely the aged memory impaired rats and the scopolamine-induced amnesia model. QR2 is a cytosolic flavoprotein that catalyzes the reduction of its substrate and enhances the production of damaging activated quinone and ROS. QR2-like immunostaining is enriched in cerebral structures associated with learning behaviors, such as the hippocampal formation and the temporofrontal cortex of rat, mouse, and human brains. In cultured rat embryonic hippocampal neurons, selective inhibitors of QR2, namely S26695 and S29434, protected against menadione-induced cell death by reversing its proapoptotic action. S26695 (8 mg/kg) also significantly inhibited scopolamine-induced amnesia. Interestingly, adult QR2 knock-out mice demonstrated enhanced learning abilities in various tasks, including Morris water maze, object recognition, and rotarod performance test. Other behaviors related to anxiety (elevated plus maze), depression (forced swim), and schizophrenia (prepulse inhibition) were not affected in QR2-deficient mice. Together, these data suggest a role for QR2 in cognitive behaviors with QR2 inhibitors possibly representing a novel therapeutic strategy toward the treatment of learning deficits especially observed in the aged brain.

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“…The overexpression observed in these diseases occurs by a polymorphism in the QR2 promoter that hampers the negative modulation of the NQO2 (the QR2 gene) [28] . In general, enzymatic overexpression through NQO2 polymorphisms has been related to familial and sporadic types of Parkinson's disease [18,29] , Alzheimer's disease [19,30,31] , methamphetamine psychosis [32] and alcoholism [33] . In the retina, results demonstrating the ability of QR2 to accumulate dopamine are also physiopathologically important because this neural tissue is affected in Parkinson's disease [34] , and assessments of the retina has been proposed to estimate the progression of this neurodegenerative diseases in humans [35] .…”

Section: Research Highlightmentioning

confidence: 99%

NRH: Quinone Reductase activity results in the accumulation of endogenous dopamine in the retina

et al. 2015

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Dopamine quinone is substrate of the NRH: Quinone Reductase enzyme (QR2) in the retina. The capability of accumulates endogenous dopamine in a neural tissue explains the association of certain neuropsychiatric diseases with polymorphisms in the QR2 promoter that causes overexpression via loss of the capability to bind repressors. However, QR2 doubly reduce other small compounds present in neural and non-neural tissues, being its physiology tissue dependent. In this context, the function of the neurohormone melatonin and analogues in the active site of this multifunctional enzyme is discussed in this mini review. The flavoenzyme Ribosyldihydronicotinamide dehydrogenase (quinone), EC 1.10.99.2 (NRH: Quinone Reductase, QR2) is an unpredicted member of the quinone reductase family of phase II detoxifying enzymes [1] because its detoxifying activity produces reactive quinones and free radicals [2] . In addition, the natural QR2 cosubstrates are NRH (N-ribosyl-dihydronicotinamide) and NMH (N-methyl-dihydronicotinamide) [3][4][5] . This enzyme is inhibited by quercetin, resveratrol, benzo[a]pyrene [3][4][5] , some protein kinases inhibitors [6,7] , antimalarial drugs [8] and many others synthetized analogues compounds [9,10] . QR2 is able to doubly reduce quinones such as menadione, a synthetic vitamin K precursor, the coenzymes Q0-10 Keywords[11] and anti-cancer pro-drugs such as CB1954 [12] . The kinetics of this 24-kDa cytosolic flavoprotein proceeds via a double displacement mechanism [13] . Through this mechanism, FAD is reduced by the cosubstrate, which then diffuses out from the binding pocket, permitting occupation of the active site by the substrate. In this type of catalysis, the excess substrate competes with the cosubstrate, or vice-versa, resulting in the inhibition of the enzyme. Therefore, the effect of small compounds in QR2 catalysis is concentration dependent. The capability to accept a myriad of quinones and small compounds as substrates turn QR2 into a multifunctional enzyme. In mammals, QR2 is present in different tissues [1,14] that contain different endogenous compounds. Additionally, each tissue is susceptible to be targeted by exogenous compounds with the ability to function as substrates for QR2 catalysis. Therefore, QR2 physiology appears to be tissue-dependent. Dopamine plays a role in light-adapting events in retinal physiology [15] , whereas in the brain, attention, memory and other cognitive processes are regulated by dopamine [16] . A great achievement in the investigation of QR2 physiology was the finding that ortho-quinones such as dopa-quinone RESEARCH HIGHLIGHT

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Association of NRH:Quinone Oxidoreductase 2 Gene Promoter Polymorphism With Higher Gene Expression and Increased Susceptibility to Parkinson's Disease

Cited by 37 publications

References 33 publications

NRH:Quinone Oxidoreductase 2 (NQO2) Protein Competes with the 20 S Proteasome to Stabilize Transcription Factor CCAAT Enhancer-binding Protein α (C/EBPα), Leading to Protection against γ Radiation-induced Myeloproliferative Disease

NRH:Quinone Oxidoreductase 2 (NQO2) Protein Competes with the 20 S Proteasome to Stabilize Transcription Factor CCAAT Enhancer-binding Protein α (C/EBPα), Leading to Protection against γ Radiation-induced Myeloproliferative Disease

Loss of Quinone Reductase 2 Function Selectively Facilitates Learning Behaviors

NRH: Quinone Reductase activity results in the accumulation of endogenous dopamine in the retina

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