The Role Of Thioredoxin In The MPP~+Induced Autophagy

Parkinson’s disease (PD) is a common neurodegenerative disease, usually occurrs in the old people. Its incidence reaches approximately1.7%in the population over the age of60years old. PD is associated with genetic and environmental factors. PD is characterized by progressive defects of substantia nigra dopaminergic neurons and mitochondrial dysfunction, alpha-synuclein misfolding, aggregation and abnormal degradation.1-methyl-4-phenyl-pyridinium ion (MPP+) is a metabolite of1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the brain, which can specifically inhibit mitochondrial complex I and induce dopaminergic neuronal death. Therefore, the cell model of PD can be made by MPP+stimulating neurons cells.Autophagy (autophagy) is one of the main pathway on the removing proteins and organelles of eukaryotic cells, and is highly conserved. Autophagy is a metabolic pathway which regulates non-selective degradation of cytoplasmic macromolecules and organelles. its biological function has been confirmed in many physiological and pathological conditions, such as hunger, clean-up of damaged proteins and organelles. removing pathogens, cell survival and death as well as inhibting tumor.Autophagy has dual functions. On the one hand, it can degrade the abnormal proteins, preventing its accumulation in neurons; the othe hand, autophagic stress can be induced by over active or low function of autophagy, which results in organelles damage, and mitochondrial dysfunction, cell death and involving in the pathogenesis of neurodegenerative diseases.Thioredoxin1(Trx-1) is a12KDa protein with redox activity. Its biological functions are antioxidant effect, the action of growth factors, inhibiting apoptosis, regulating transcription factor activity, mediating protein folding and inflammatory response. The overexpression of Trx-1resists dopaminergic neuronal damage by MPTP, thus Trx-1is a target for therapy on Parkinson’s disease.We used MPP+to stimulate rat pheochromocytoma (PC12) cells to build a cell model of PD and to study the role of Trx-1in autophagy induced by MPP+, to further charify the mechansim on PD and provide new potential targets for the treatment of PD.The main findings are as follows:the neurotoxic drugs MPP+dose-dependently reduced the vitality of PC12cells. Meanwhile, after short-term, long-term treatment with MPP+, the expressions of Trx-1and LC3-Ⅱ/LC3-Ⅰ were detected in PC12cells. The results suggested that MPP+not only time-dependently reduced the expression of Trx-1, and LC3-Ⅱ/LC3-I expression was increased time-dependently. In the MPP+induced PD model, the inducer of autophagy can protect cells from MPP+-induced damage, while the inhibitor of autophagy can promote the apoptosis induced by MPP+. The Trx-1siRNA can promote apoptosis mediated by MPP+in PC12cells, and overexpression of Trx-1can protect cells from MPP+-mediated toxicity in PC12cell, in which LC3-II/LC3-I exoressions are affected. All of these indicate that Trx-1may protect PC12cells from MPP+cytotoxicity by increasing cell autophagy.