Department of Biomedical Science, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota, USA.
FASEB J. 2018 Mar;32(3):1640-1652. doi: 10.1096/fj.201700662RR. Epub 2018 Jan 3.
Alterations in Ca homeostasis affect neuronal survival. However, the identity of Ca channels and the mechanisms underlying neurotoxin-induced neuronal degeneration are not well understood. In this study, the dopaminergic neurotoxins 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridium ions (MPP)/1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which mimic Parkinson's disease (PD), induced neuronal degeneration by decreasing store-mediated Ca entry. The function of the transient receptor potential canonical (TRPC)-1 channel was decreased upon exposure to the neurotoxins, followed by a decrease in TRPC1 expression. Similar to neurotoxins, samples from patients with PD exhibited attenuated TRPC1 expression, which was accompanied by a decrease in autophagic markers and a subsequent increase in apoptosis markers. Furthermore, exposure to neurotoxins attenuated PKC phosphorylation, decreased expression of autophagic markers, and increased apoptosis in SHSY-5Y neuroblastoma cells, which was again dependent on TRPC1. Prolonged neurotoxin treatment attenuated the binding of NF-κB to the TRPC1 promoter, which resulted in a decrease in TRPC1 expression, thereby attenuating autophagy and activating cell death. Restoration of TRPC1 expression rescued the effects of the dopaminergic neurotoxins in neuroblastoma cells by increasing Ca entry, restoring NF-κB activity, and promoting autophagy. Overall, these results suggest that dopaminergic neurotoxins initially decreased Ca entry, which inhibited the binding of NF-κB to the TRPC1 promoter, thereby inhibiting TRPC1 expression and resulting in cell death by preventing autophagy.-Sukumaran, P., Sun, Y., Antonson, N., Singh, B. B. Dopaminergic neurotoxins induce cell death by attenuating NF-κB-mediated regulation of TRPC1 expression and autophagy.
钙稳态的改变会影响神经元的存活。然而，钙通道的特性以及神经毒素诱导神经元退化的机制尚不清楚。在这项研究中，多巴胺能神经毒素 6-羟多巴胺（6-OHDA）和 1-甲基-4-苯基吡啶鎓离子（MPP）/1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）模拟了帕金森病（PD），通过减少储存介导的钙内流诱导神经元退化。暴露于神经毒素后，瞬时受体电位经典（TRPC）-1 通道的功能降低，随后 TRPC1 表达减少。与神经毒素相似，来自 PD 患者的样本显示 TRPC1 表达减弱，同时自噬标记物减少，随后凋亡标记物增加。此外，暴露于神经毒素会减弱 PKC 磷酸化，减少自噬标记物的表达，并增加 SHSY-5Y 神经母细胞瘤细胞的凋亡，这再次依赖于 TRPC1。延长神经毒素处理会减弱 NF-κB 与 TRPC1 启动子的结合，导致 TRPC1 表达减少，从而减弱自噬并激活细胞死亡。TRPC1 表达的恢复通过增加钙内流、恢复 NF-κB 活性和促进自噬来挽救多巴胺能神经毒素对神经母细胞瘤细胞的作用。总的来说，这些结果表明，多巴胺能神经毒素最初降低钙内流，抑制 NF-κB 与 TRPC1 启动子的结合，从而抑制 TRPC1 表达，并通过阻止自噬导致细胞死亡。
