Reduced neuronal expression of ribose‐5‐phosphate isomerase enhances tolerance to oxidative stress, extends lifespan, and attenuates polyglutamine toxicity in <i>Drosophila</i>

Wang, Ching-Tzu; Chen, Yi‐Chun; Wang, Yi-Yun; Huang, Ming-Jer; Yen, Tzu-Li; Li, Hsun; Liang, Cyong-Jhih; Sang, Tzu-Kang; Ciou, Shih‐Ci; Yuh, Chiou-Hwa; Wang, Chao-Yung; Brummel, Theodore J.; Wang, Horng-Dar

doi:10.1111/j.1474-9726.2011.00762.x

Cited by 27 publications

(30 citation statements)

References 48 publications

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“…4C). Notably, silencing of either of the two enzymes also significantly ameliorated shortened median life span in Aβ 42 flies from 54 d to 66 d and 68 d, respectively (P < 0.001, Fig. 4D).…”

Section: Kmo and Tdo Inhibition Ameliorates Disease Phenotypes In Flymentioning

confidence: 95%

“…The availability of new TDO inhibitors (49,50), and access to the crystal structures of both TDO (51) and KMO (52), should allow further testing of these hypotheses in the near future. 42 panneuronally. Both aSyn (E) and Aβ 42 (F) reduce climbing performance, and the effects are reversed by down-regulation of v and cn.…”

Section: Discussionmentioning

confidence: 99%

“…elavGAL4-driven aSyn, Aβ 42 ,and Aβ 42Arc flies exhibited a reduction in climbing at all of the posteclosion ages tested (Fig. 4 E and F and SI Appendix, Fig.…”

Section: Kmo and Tdo Inhibition Ameliorates Disease Phenotypes In Flymentioning

confidence: 99%

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Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites

Breda

Sathyasaikumar

Idrissi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

123

128

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Metabolites of the kynurenine pathway (KP) of tryptophan (TRP) degradation have been closely linked to the pathogenesis of several neurodegenerative disorders. Recent work has highlighted the therapeutic potential of inhibiting two critical regulatory enzymes in this pathway-kynurenine-3-monooxygenase (KMO) and tryptophan-2,3-dioxygenase (TDO). Much evidence indicates that the efficacy of KMO inhibition arises from normalizing an imbalance between neurotoxic [3-hydroxykynurenine (3-HK); quinolinic acid (QUIN)] and neuroprotective [kynurenic acid (KYNA)] KP metabolites. However, it is not clear if TDO inhibition is protective via a similar mechanism or if this is instead due to increased levels of TRP-the substrate of TDO. Here, we find that increased levels of KYNA relative to 3-HK are likely central to the protection conferred by TDO inhibition in a fruit fly model of Huntington's disease and that TRP treatment strongly reduces neurodegeneration by shifting KP flux toward KYNA synthesis. In fly models of Alzheimer's and Parkinson's disease, we provide genetic evidence that inhibition of TDO or KMO improves locomotor performance and ameliorates shortened life span, as well as reducing neurodegeneration in Alzheimer's model flies. Critically, we find that treatment with a chemical TDO inhibitor is robustly protective in these models. Consequently, our work strongly supports targeting of the KP as a potential treatment strategy for several major neurodegenerative disorders and suggests that alterations in the levels of neuroactive KP metabolites could underlie several therapeutic benefits.T he kynurenine pathway (KP), the major catabolic route of tryptophan (TRP) metabolism in mammals ( Fig. 1), has been closely linked to the pathogenesis of several brain disorders (1). This pathway contains several neuroactive metabolites, including 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN) and kynurenic acid (KYNA) (2). QUIN is a well-characterized endogenous neurotoxin that specifically activates N-methyl-D-aspartate (NMDA) receptors, thereby inducing excitotoxicity (3, 4). The metabolites 3-HK and QUIN are also neurotoxic via the generation of free radicals and oxidative stress (5, 6). Conversely, KYNA-synthesized by kynurenine aminotransferases (KATs)-is neuroprotective through its antioxidant properties and antagonism of both the α7 nicotinic acetylcholine receptor and the glycine coagonist site of the NMDA receptor (7-13). Levels of these metabolites are regulated at two critical points in the KP: (i) the initial, rate-limiting conversion of TRP into N-formylkynurenine by either tryptophan-2,3-dioxygenase (TDO) or indoleamine-2,3-dioxygenase 1 and 2 (IDO1 and IDO2); and (ii) synthesis of 3-HK from kynurenine by the flavoprotein kynurenine-3-monoxygenase (KMO) (1).Alterations in levels of the KP metabolites have been observed in a broad range of brain disorders, including both neurodegenerative and psychiatric conditions (14). In neurodegenerative diseases such as Huntington's (HD), Parkinson's (PD), and Alzheimer's...

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Section: Kmo and Tdo Inhibition Ameliorates Disease Phenotypes In Flymentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites

Breda

Sathyasaikumar

Idrissi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

123

128

View full text Add to dashboard Cite

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“…Other candidates from screens that have yet to be tested in mammalian systems are TCF, a protein involved in Wnt signaling, rpi, a metabolic enzyme, TDO, a member of the M a n u s c r i p t 13 kynurenine pathway, Tra1, a component of the HAT complex, and DJ-1α, an oxidationsensitive chaperone protein (Campesan et al, 2011;Dupont et al, 2012;Sajjad et al, 2014;Wang et al, 2012;Zhang et al, 2010). Considering the successful translation of many other candidates discovered or validated in Drosophila models of HD (Table 2), these remain prime candidates for evaluation in mammalian systems.…”

Section: High Throughput Screening Techniques For Drosophila Models Omentioning

confidence: 99%

Using Drosophila models of Huntington's disease as a translatable tool

Lewis

Smith

2016

Journal of Neuroscience Methods

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“…Furthermore, Resveratrol, the plant polyphenol found in grape berry skin has been shown to increase lifespan in the same model organism (Bass et al, 2007), the same phenomenon same goes for Pomegranate juice and Bacopa monnieri, whose phytoconstituents have been shown to regulate cellular oxidative stress in Drosophila (Balasubramani et al, 2014;Subramanian et al, 2014). The mechanism by which the reported plant products enhances longevity is in their modulation of oxidative stress and their role in acting as dietary restriction mimetic in the nutrient sensing pathways (Wang et al, 2012).…”

Section: Resultsmentioning

confidence: 99%

Retraction: Ananas Sativa Increases Longevity Through Oxidative Stress Resistance in Drosophila Melanogaster

Ajagun-Ogunleye

2018

Afr J Tradit Complement Altern Med

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Background: Ageing is the major risk factor for most non-communicable diseases. It occurs as a result of free radical damage to macromolecules in the cell, coupled with environmental stress assaults. In the quest to identify new anti-ageing bioactive compounds from natural products, and despite the therapeutic values of Ananas sativa, its anti-ageing activity has not been fully elucidated. Therefore, the aim of this study was to screen the crude, methanol fruit extract of Ananas sativa (MEAS) and its fractions, for anti-ageing bioactivity in the fruit fly, Drosophila melanogaster w 1118 wild type flies. Materials and Methods: Flies reared on food supplemented with 5, 10, and 20mg/ml fruit pulp and juice extract were assayed for longevity, fertility and stress resistance according to established protocols. Phytochemical composition and scavenging activity of extract on 2,2-diphenyl-1-picrylhydrazyl free radical (DPPH) were equally evaluated. The crude extract anti-ageing activity was assayed through a successive bioassay-guided fractionation approach, with different extraction solvents; n-Hexane, Chloroform, Ethyl acetate and Acetone. Results: There was a dose-dependent effect of the fruit extract on lifespan, fertility and oxidative stress resistance, with a unique information on the anti-ageing bioactivity of Ananas sativa. The IC 50 values of the fruit extract and Ascorbic acid positive control in the free radical scavenging activity were 248.15µg/ml and 81.51µg/ml respectively. However, the bioactive fraction obtained from the Ethylacetate fraction F1, did not exhibit oxidative stress resistant effect in the model organism. Conclusion:The methanol fruit extract of Ananas sativa possesses anti-ageing bioactivity through oxidative stress resistance.

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Reduced neuronal expression of ribose‐5‐phosphate isomerase enhances tolerance to oxidative stress, extends lifespan, and attenuates polyglutamine toxicity in Drosophila

Cited by 27 publications

References 48 publications

Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites

Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites

Using Drosophila models of Huntington's disease as a translatable tool

Retraction: Ananas Sativa Increases Longevity Through Oxidative Stress Resistance in Drosophila Melanogaster

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