Abstract
Parkinson's disease (PD) is a progressive nervous system disorder. Until now, the molecular mechanism of its occurrence is not fully understood. Paraquat (PQ) was identified as a neurotoxicant and is linked to increased PD risk and PD-like neuropathology. Ferroptosis is recognized as a new form of regulated cell death. Here, we revealed a new underlying mechanism by which ferritinophagy-mediated ferroptosis is involved in PD induced by PQ. The effect of PQ on movement injury in mice was investigated by the bar fatigue and pole-climbing test. SH-SY5Y human neuroblastoma cells were used to evaluate the mechanism of ferroptosis. Our results showed that PQ induced movement injury by causing the decrease in tyrosine hydroxylase in mice. In vitro, PQ significantly caused the iron accumulation in cytoplasm and mitochondria through ferritinophagy pathway induced by NCOA4. Iron overload initiated lipid peroxidation through 12Lox, further inducing ferroptosis by producing lipid ROS. PQ downregulated SLC7A11 and GPX4 expression and upregulated Cox2 expression significantly, which were important markers in ferroptosis. Fer-1, an inhibitor of ferroptosis, could significantly ameliorate the ferroptosis induced by PQ. Meanwhile, Bcl2, Bax, and p-38 were involved in apoptosis induced by PQ. In conclusion, ferritinophagy-mediated ferroptosis pathway played an important role in PD occurrence. Bcl2/Bax and P-p38/p38 pathways mediated the cross-talk between ferroptosis and apoptosis induced by PQ. These data further demonstrated the complexity of PD occurrence. The inhibition of the ferroptosis and apoptosis together may be a new strategy for the prevention of neurotoxicity or PD in the future.
Highlights
Parkinson’s disease (PD) is the most frequent and debilitating group of motor disorders in the elderly population [1, 2] and has affected millions around the world from 1990 to 2015 [3]
The results showed that the latency to fall and the time staying on the pole of PQ group were significantly different from that of the control group from the fourth day of testing as shown in Figures 1(a) and 1(b)
In order to find which pathway mediated the cross-talk between ferroptosis and apoptosis induced by PQ, we evaluated the expressions Bcl2, Bax, -p38 mitogen-activated protein kinases (P-p38), and p38
Summary
Parkinson’s disease (PD) is the most frequent and debilitating group of motor disorders in the elderly population [1, 2] and has affected millions around the world from 1990 to 2015 [3]. The neuropathological features of PD are the loss of dopaminergic neurons in vulnerable brain regions, especially in the substantia nigra (SN) [4, 5]. Metabolic disorders of metal ions, oxidative stress, mitochondrial dysfunction, inflammation, and apoptotic processes have been implicated in PD [6,7,8,9,10]. There is no cure for PD because the molecular mechanism of PD has not yet been fully understood. An understanding of the mechanisms of PD may play an important role in the prevention and treatment of PD occurrence
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