Drosophila eye color mutants as therapeutic tools for Huntington disease

Green, Edward W.; Campesan, Susanna; Breda, Carlo; Sathyasaikumar, Korrapati V.; Muchowski, Paul J.; Schwarcz, Robert; Kyriacou, Charalambos P.; Giorgini, Flaviano

doi:10.4161/fly.19999

Cited by 33 publications

(30 citation statements)

References 24 publications

(34 reference statements)

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“…Feeding flies by 3HOK alone, in the absence of mutant HTT, did not cause neurodegeneration [14]. Thus, the high level of 3HOK is toxic, yet, it may be not sufficient for neurodegeneration which also requires the additional factors, such as the lack of neuroprotectant KYNA.…”

Section: Discussionmentioning

confidence: 99%

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Antioxidant Properties of Kynurenines: Density Functional Theory Calculations

et al. 2016

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Kynurenines, the main products of tryptophan catabolism, possess both prooxidant and anioxidant effects. Having multiple neuroactive properties, kynurenines are implicated in the development of neurological and cognitive disorders, such as Alzheimer's, Parkinson's, and Huntington's diseases. Autoxidation of 3-hydroxykynurenine (3HOK) and its derivatives, 3-hydroxyanthranilic acid (3HAA) and xanthommatin (XAN), leads to the hyperproduction of reactive oxygen species (ROS) which damage cell structures. At the same time, 3HOK and 3HAA have been shown to be powerful ROS scavengers. Their ability to quench free radicals is believed to result from the presence of the aromatic hydroxyl group which is able to easily abstract an electron and H-atom. In this study, the redox properties for kynurenines and several natural and synthetic antioxidants have been calculated at different levels of density functional theory in the gas phase and water solution. Hydroxyl bond dissociation enthalpy (BDE) and ionization potential (IP) for 3HOK and 3HAA appear to be lower than for xanthurenic acid (XAA), several phenolic antioxidants, and ascorbic acid. BDE and IP for the compounds with aromatic hydroxyl group are lower than for their precursors without hydroxyl group. The reaction rate for H donation to *O-atom of phenoxyl radical (Ph-O*) and methyl peroxy radical (Met-OO*) decreases in the following rankings: 3HOK ~ 3HAA > XAAOXO > XAAENOL. The enthalpy absolute value for Met-OO* addition to the aromatic ring of the antioxidant radical increases in the following rankings: 3HAA* < 3HOK* < XAAOXO* < XAAENOL*. Thus, the high free radical scavenging activity of 3HAA and 3HOK can be explained by the easiness of H-atom abstraction and transfer to O-atom of the free radical, rather than by Met-OO* addition to the kynurenine radical.

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Section: Discussionmentioning

confidence: 99%

“…Since 3HOK is capable of auto-condensation, the eyes of this mutant, as well as the color of mammalian lens cataract [13] progressively get brown on ageing. The Drosophila eye color mutants are started to be envisioned as a therapeutic tools for HD [14]. …”

Section: Introductionmentioning

confidence: 99%

Antioxidant Properties of Kynurenines: Density Functional Theory Calculations

et al. 2016

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“…[7] (1-methyl-TRP is not approved for human use, and had high toxicity in Drosophila (our unpublished data)). Recent studies indicate that genetic inhibition of TDO was protective against the eclosion defect in Drosophila model of Huntington's disease (flies with impaired TRP-KYN metabolism) [20]. The increased dioxygenation of mitochondrial TRP to N-formylKYN was consistently present among conserved biomarkers across ageing models in five species [21].…”

Section: Discussionmentioning

confidence: 99%

Berberine Prolongs Life Span and Stimulates Locomotor Activity of <i>Drosophila melanogaster</i>

Navrotskaya¹,

Oxenkrug

Vorobyova³

et al. 2012

AJPS

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Drosophila melanogaster mutants with deficient kynurenine (KYN) formation from tryptophan (TRP) have longer life span than wild type flies. Administration of alpha-methyl-TRP and 5-methyl-TRY, the inhibitors of TRP-KYN metabolism, prolonged life span in wild-type flies. Both inhibitors are not available for human use. Berberine, an isoquinoline alkaloid isolated from Berberis aristata, is known as the herb widely used in traditional Chinese and Indian medicine. Berberin is a strong inhibitor of the enzyme catalyzing TRP conversion into KYN. Considering this particular feature we investigated the effect of berberine on life- and health-span in wild-type Drosophila melanogaster. The results of our study showed that Berberine extended mean, median and maximum life span of female flies. Berberine did not affect the number of pupae of filial generation and decreased their lethality. Berberine increased locomotor activity (vertical climbing). The results of the study suggest that berberine prolongs life- and improves health-span of Drosophila melanogaster. Berberine might be a candidate drug for prevention and treatment of aging and aging-associated medical and psychiatric disorders.

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“…Several studies have also found perturbation in KP metabolites in the blood and cerebrospinal fluid of patients with AD, with decreased levels of KYNA correlating with reduced cognitive performance (18,19). Similarly, in the basal ganglia of patients with PD, a reduction in KYNA levels combined with increased 3-HK has been observed (20,21).Drosophila melanogaster has provided a useful model for interrogation of the KP in both normal physiology and in neurodegenerative disease (22,23). In fruit flies, TDO and KMO are encoded by vermillion (v) and cinnabar (cn), respectively, and both are implicated in Drosophila eye color pigmentation and brain plasticity (24,25).…”

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confidence: 99%

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.

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118

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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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Drosophila eye color mutants as therapeutic tools for Huntington disease

Cited by 33 publications

References 24 publications

Antioxidant Properties of Kynurenines: Density Functional Theory Calculations

Antioxidant Properties of Kynurenines: Density Functional Theory Calculations

Berberine Prolongs Life Span and Stimulates Locomotor Activity of <i>Drosophila melanogaster</i>

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

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Drosophila eye color mutants as therapeutic tools for Huntington disease

Cited by 33 publications

References 24 publications

Antioxidant Properties of Kynurenines: Density Functional Theory Calculations

Antioxidant Properties of Kynurenines: Density Functional Theory Calculations

Berberine Prolongs Life Span and Stimulates Locomotor Activity of &lt;i&gt;Drosophila melanogaster&lt;/i&gt;

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

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Berberine Prolongs Life Span and Stimulates Locomotor Activity of <i>Drosophila melanogaster</i>