Department of Neurosurgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, P.R. China.
CNS Neurosci Ther. 2024 Mar;30(3):e14441. doi: 10.1111/cns.14441. Epub 2023 Sep 22.
The feature of Parkinson's disease (PD) is the heavy dopaminergic neuron loss of substantia nigra pars compacta (SNpc), while glutaredoxin (GLRX) has been discovered to modulate the death of dopaminergic neurons. In this context, this study was implemented to uncover the impact of GRX1 on motor dysfunction and dopamine neuron degeneration in PD mice and its potential mechanism.
A PD mouse model was established via injection with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into mice. After gain- and loss-of-function assays in mice, motor coordination was assessed using rotarod, pole, and open-field tests, and neurodegeneration in mouse SNpc tissues was determined using immunohistochemistry of tyrosine hydroxylase and Nissl staining. NRF1, methyltransferase-like 3 (METTL3), and GLRX expression in SNpc tissues were evaluated using qRT-PCR, Western blot, and immunohistochemistry. The N6-methyladenosine (m A) levels of GLRX mRNA were examined using MeRIP. The relationship among NRF1, METTL3, and GLRX was determined by RIP, ChIP, and dual luciferase assays.
Low GLRX, METTL3, and NRF1 expression were observed in MPTP-induced mice, accompanied by decreased m A modification level of GLRX mRNA. GLRX overexpression alleviated motor dysfunction and dopamine neuron degeneration in MPTP-induced mice. METTL3 promoted m A modification and IGF2BP2-dependent stability of GLRX mRNA, and NRF1 increased METTL3 expression by binding to METTL3 promoter. NRF1 overexpression increased m A modification of GLRX mRNA and repressed motor dysfunction and dopamine neuron degeneration in MPTP-induced mice, which was counteracted by METTL3 knockdown.
Conclusively, NRF1 constrained motor dysfunction and dopamine neuron degeneration in MPTP-induced PD mice by activating the METTL3/GLRX axis.
帕金森病（PD）的特征是黑质致密部（SNpc）中多巴胺能神经元大量丢失，而谷氧还蛋白（GLRX）已被发现可调节多巴胺能神经元的死亡。在这种情况下，本研究旨在揭示 GRX1 对 PD 小鼠运动功能障碍和多巴胺神经元退化的影响及其潜在机制。
通过向小鼠注射 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）建立 PD 小鼠模型。在小鼠进行功能获得和功能丧失实验后，使用转棒、棒和旷场试验评估运动协调能力，并用酪氨酸羟化酶和尼氏染色的免疫组织化学法测定小鼠 SNpc 组织中的神经退行性变。使用 qRT-PCR、Western blot 和免疫组织化学法评估 SNpc 组织中 NRF1、甲基转移酶样 3（METTL3）和 GLRX 的表达。使用 MeRIP 检测 GLRX mRNA 的 N6-甲基腺苷（m A）水平。通过 RIP、ChIP 和双荧光素酶测定确定 NRF1、METTL3 和 GLRX 之间的关系。
在 MPTP 诱导的小鼠中观察到 GLRX、METTL3 和 NRF1 表达降低，同时 GLRX mRNA 的 m A 修饰水平降低。GLRX 过表达缓解了 MPTP 诱导的小鼠的运动功能障碍和多巴胺神经元退化。METTL3 促进 GLRX mRNA 的 m A 修饰和 IGF2BP2 依赖性稳定性，NRF1 通过结合 METTL3 启动子增加 METTL3 的表达。NRF1 过表达增加 GLRX mRNA 的 m A 修饰并抑制 MPTP 诱导的小鼠的运动功能障碍和多巴胺神经元退化，而 METTL3 敲低则逆转了这一作用。
总之，NRF1 通过激活 METTL3/GLRX 轴来抑制 MPTP 诱导的 PD 小鼠的运动功能障碍和多巴胺神经元退化。
