Drosophila eye color mutants as therapeutic tools for Huntington disease.
Huntington disease (HD) is a fatal inherited neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin protein (htt). A pathological hallmark of the disease is the loss of a specific population of striatal neurons, and considerable attention has been paid to the role of the kynurenine pathway (KP) of tryptophan (TRP) degradation in this process. The KP contains three neuroactive metabolites: 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN), and kynurenic acid (KYNA). 3-HK and QUIN are neurotoxic, and are increased in the brains of early stage HD patients, as well as in yeast and mouse models of HD. Conversely, KYNA is neuroprotective and has been shown to be decreased in HD patient brains. We recently used a Drosophila model of HD to measure the neuroprotective effect of genetic and pharmacological inhibition of kynurenine monoxygenase (KMO)-the enzyme catalyzing the formation of 3-HK at a pivotal branch point in the KP. We found that KMO inhibition in Drosophila robustly attenuated neurodegeneration, and that this neuroprotection was correlated with reduced levels of 3-HK relative to KYNA. Importantly, we showed that KP metabolites are causative in this process, as 3-HK and KYNA feeding experiments modulated neurodegeneration. We also found that genetic inhibition of the upstream KP enzyme tryptophan-2,3-dioxygenase (TDO) was neuroprotective in flies. Here, we extend these results by reporting that genetic impairment of KMO or TDO is protective against the eclosion defect in HD model fruit flies. Our results provide further support for the possibility of therapeutic KP interventions in HD.
Department of Genetics, University of Leicester, Leicestershire, UK.
Edward W
EW
Green
Susanna
S
Campesan
Carlo
C
Breda
Korrapati V
KV
Sathyasaikumar
Paul J
PJ
Muchowski
Robert
R
Schwarcz
Charalambos P
CP
Kyriacou
Flaviano
F
Giorgini
D000818:Animals; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics; D004331:Drosophila melanogaster / Q000235:genetics*; D005127:Eye Color / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics; D005260:Female; D055785:Gene Knockdown Techniques; D006816:Huntington Disease / Q000378:metabolism* / Q000628:therapy; D007736:Kynurenic Acid / Q000378:metabolism; D007737:Kynurenine / Q000031:analogs & derivatives / Q000378:metabolism; D050601:Kynurenine 3-Monooxygenase / Q000037:antagonists & inhibitors* / Q000235:genetics; D008297:Male; D014366:Tryptophan Oxygenase / Q000235:genetics
D029721:Drosophila Proteins; D005136:Eye Proteins; C005045:3-hydroxykynurenine; D007737:Kynurenine; D014366:Tryptophan Oxygenase; C121974:v protein, Drosophila; D050601:Kynurenine 3-Monooxygenase; D007736:Kynurenic Acid