Thioredoxin-1 decreases alpha-synuclein induced by MPTP through promoting autophagy-lysosome pathway

Abstract Parkinson’s disease (PD) is characterized by Lewy body. Alpha-synuclein (α-syn) is a major component of Lewy body. Autophagy eliminates damaged organelles and abnormal aggregated proteins. Thioredoxin-1 (Trx-1) is a redox regulating protein and plays roles in protecting neurons against neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). However, the relationship between Trx-1 and α-syn in PD is still unknown. The movement disorder and dopaminergic neurotoxicity in MPTP PD mice were improved by Trx-1 overexpression, whereas were aggravated by Trx-1 knockdown in the substantia nigra pars compacta (SNpc) in mice. α-syn was increased in MPTP PD mice, which was inhibited by Trx-1 overexpression, whereas was exacerbated in Trx-1 knockdown mice. The autophagosomes were increased by MPTP, which were recovered in Trx-1 overexpressing mice, while were further increased in Trx-1 knockdown in the SNpc in mice under electron microscope. The expressions of phosphatase and tensin homolog deleted on chromosome ten (PTEN)-induced putative kinase 1 (PINK1), Parkin, LC3 II and p62 were induced by MPTP, which were blocked in Trx-1 overexpressing mice, which were further increased in Trx-1 knockdown mice. Cathepsin D was decreased by MPTP, which was restored in Trx-1 overexpressing mice, while was further decreased in Trx-1 knockdown mice. The mRFP-GFP-LC3 green fluorescent dots were increased by 1-methyl-4-phenylpyridinium (MPP+) and more green fluorescent dots in Trx-1 siRNA transfection in PC 12 cells, but mRFP-GFP-LC3 red fluorescent dots were increased in Trx-1 overexpressing cells. These results indicate that Trx-1 may eliminate α-syn in PD mice through potentiating autophagy-lysosome pathway.