The Molecular Mechanism On Thioredoxin-1 Regulating Autophagy In Parkinson’ Disease

Parkinson’s disease (PD) is a common neurodegenerative disease and associated with genetic and environmental factors. The main pathological characteristics of PD are a large number of dopaminergic neurons’s missing and significant reduction of dopamine in the midbrain substantia nigra pars compacta (SNpc), and accompanied by the cytoplasm Lewy body(LB)s accumulation. Its pathogenesis is complex, which is involved in oxidative stress and Endoplasmic Reticulum(ER) stress.Autophagy is one of the important metabolic pathways in eukaryotic cells, by which superflous or damged proteins and organelles are degraded by lysosomes. Autophagy progress includes 5 step, initiation, extension, autophagosome formation, fusion, autophagolysosome maturation. Its mechanism is complex which is releted with a serious of Autophagy-related genes (ATGs), oxidative stress and ER stress. Autophagy plays an important role in maintaining the dynamic balance and involved in various diseases. In recent years, studies have shown that autophagy also plays an important role in Parkinson’s disease, however, its mechanism is still unknown.Thioredoxin-1(Trx-1) is a redox regulating protein. It has been reported that Trx-1 protects neurons and inhibits PD by suppressing the endoplasmic reticulum stress induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPP+)/ 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). It has not been reported that Trx-1 regulates autophagy in PD. This study will explore the role and mechanism of Trx-1 regulating autophagy in PD by taking Trx-1 as a target and by using siRNA Trx-1 injection in SNpc and Trx-1 overexpression transgenic mice. The main results were as follows:(1) The downregulation of Trx-1 expression in SNpc in mice aggravated the PD symptoms caused by MPTP. The movement of disorder and limbs injury caused by MPTP in mice of Trx-1 siRNA injection in SNpc were more serious when compared to the control group, and apoptosis of dopaminergic neurons in SNpc is more serious.(2) The downregulation of Trx-1 expression in SNpc aggravated dysfunction of autophagy caused by MPTP. The expressions of DJ-1 and cathepsinD were decreased by MPTP in mice of Trx-1 siRNA injection in SNpc when compared to the control group.(3) Trx-1 overexpression improved the symptoms of PD caused by MPTP. The movement of disorder and limbs injury caused by MPTP in mice of Trx-1 overexpression were inhibited when compared to the control group, and apoptosis of dopaminergic neurons in SNpc was suppressed.(4) Trx-1 overexpression improved the dysfunction of autophagy induced by MPTP. The expressions of DJ-1 and cathepsinD were restored in Trx-1 overexpression mice, ATG4B expression were increased in Trx-1 overexpression.These data suggest that downregulation of Trx-1 may decrease further basal level of autophagy and promote MPP+/MPTP-induced dopaminergic toxicity and overexpression of Trx-1 may increase further basal level of autophagy and suppress MPP+/MPTP-induced dopaminergic toxicity.In conclusion, this study explored the molecular mechanism of Trx-1 regulating autophagy in PD by using Trx-1 downregulation in SNpc and Trx-1 overexpression transgenic mice. We get the conclusion from the results of this study:Trx-1 improves the activity of autophagy in PD by regulating the expressions of DJ-1, Atg4B, and cathepsinD and then reduces the MPTP-induced toxicity.