Thioredoxin-1 Inhibits Golgi Stress Induced by Methyl-4-Phenyl-1,2,3, 6-Tetrahydropyridine

Aims: Parkinson’s disease (PD) is a common neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and the aggregation of alpha-synuclein (α-syn) in Lewy bodies. Emerging studies find that disruption of the Golgi structure and Golgi stress are involved in PD. Thioredoxin-1 (Trx-1) is a redox regulatory protein that protects DA neurons from methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP) damage. However, whether Trx-1 can protect DA neurons against MPTP-induced Golgi stress is still unknown. Results: We first made sure that MPTP led to the loss of DA neurons in the SNpc and motor impairment in mice, which was reversed in Trx-1 overexpression mice. Trx-1 overexpression suppressed Golgi apparatus fragmentation, α-syn aggregation, oxidative stress, and protein kinase C zeta expression increased by MPTP. Trx-1 overexpression restored the colocalization of Trx-1 and tyrosine hydroxylase with Golgi matrix protein 130 (GM130), decreased by MPTP. Moreover, Trx-1 overexpression suppressed the increased co-localization of Leucine-rich repeat kinase 2 and Ras-associated binding protein 29 with vacuolar protein sorting-associated protein 52 induced by MPTP. Trx-1 overexpression suppressed the expression changes of ADP-ribosylation factor 4 and heat shock protein 47, and their colocalization with GM130 induced by MPTP. Innovation: Our study reveals a novel mechanism, whereby Trx-1 inhibits Golgi stress in DA neuron induced by MPTP. Conclusions: These results suggest that Trx-1 may regulate the development of PD through inhibiting Golgi stress and is a potential new molecular target and therapeutic strategy for Golgi stress involved in PD. Antioxid. Redox Signal. 00, 000–000.