Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites.
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.
Department of Genetics, University of Leicester, Leicester LE1 7RH, United Kingdom;
Carlo
C
Breda
Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21228.
Korrapati V
KV
Sathyasaikumar
Department of Genetics, University of Leicester, Leicester LE1 7RH, United Kingdom;
Shama
S
Sograte Idrissi
Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21228.
Francesca M
FM
Notarangelo
Department of Genetics, University of Leicester, Leicester LE1 7RH, United Kingdom;
Jasper G
JG
Estranero
Department of Genetics, University of Leicester, Leicester LE1 7RH, United Kingdom;
Gareth G L
GG
Moore
Department of Genetics, University of Leicester, Leicester LE1 7RH, United Kingdom;
Edward W
EW
Green
Department of Genetics, University of Leicester, Leicester LE1 7RH, United Kingdom;
Charalambos P
CP
Kyriacou
Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21228.
Robert
R
Schwarcz
Department of Genetics, University of Leicester, Leicester LE1 7RH, United Kingdom; fg36@le.ac.uk.
Flaviano
F
Giorgini
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004330:Drosophila; D007737:Kynurenine / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome; D014366:Tryptophan Oxygenase / Q000037:antagonists & inhibitors*
D018696:Neuroprotective Agents; D007737:Kynurenine; D014366:Tryptophan Oxygenase
Alzheimer’s disease; KMO; Parkinson’s disease; TDO; neurodegeneration