Thioredoxin suppresses Parkin-associated endothelin receptor-like receptor-induced neurotoxicity and extends longevity in Drosophila.

Parkin-associated endothelin receptor-like receptor (Pael-R) is a substrate of the E3 ubiquitin ligase Parkin, which has been implicated in the pathogenesis of Parkinson disease. Misexpression of human Pael-R in Drosophila has been shown to induce selective loss of dopaminergic neurons, a symptom of Parkinson disease. Using this model, we investigated whether thioredoxin (TRX), an evolutionarily conserved antioxidant and molecular chaperone, could suppress the neurotoxicity induced by Pael-R. The Drosophila genome contains three TRX-encoding genes, namely TrxT, Trx-2, and dhd. When each of the TRX genes was overexpressed together with Pael-R in all neurons, the number of dopaminergic neurons and level of locomotor activity were significantly increased compared with control flies. To assess the role of the antioxidant activity of TRX in this context, we generated redox-defective mutants, TrxT(C35A) and TrxT(D26A/K57I), and coexpressed each of them with Pael-R. The mutants suppressed the Pael-R neurotoxicity similarly to wild-type TrxT, although the extent of the rescue was slightly reduced for the locomotor activity. We confirmed that both mutants remained active as chaperones, suggesting that this activity may be the major cause of the suppression. In the absence of Pael-R, overexpression of TRX in all neurons increased the level of locomotor activity in aged flies and extended the mean longevity by 15%. Furthermore, overexpression of TRX suppressed neurotoxicity in a Drosophila model of Machado-Joseph disease expressing polyglutamine. These results establish that Drosophila TRX can function as an anti-aging agent and as a suppressor of Pael-R- and poly-glutamine-induced neurotoxicity.