Does Thioredoxin-1 Prevent Mitochondria- and Endoplasmic Reticulum-Mediated Neurotoxicity of 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine?

We show that 1-methyl-4-phenylpyridinium ion (MPP⁺), an active metabolite of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP), induces cytotoxicity via endoplasmic reticulum (ER)- and mitochondria–mediated pathways, and thioredoxin-1 (TRX-1), a redox-active protein, prevents MPTP-induced neurotoxicity. TRX-1 overexpression suppressed reactive oxygen species and the ATP decline caused by MPP⁺ in HepG2 cells. MPP⁺ activated caspase-12 in PC12 cells and induced cytotoxicity in HeLa-ρ⁰ cells lacking mitochondrial DNA, as well as in the parental HeLa-S3 cells. TRX-1–transgenic mice demonstrated significant resistance to caspase-12 activation and the apoptotic decrease of dopaminergic neurons after MPTP administration, compared with wild-type C57BL/6 mice.