The progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) correlates with rupture of lysosome in Parkinson's disease (PD). It has been found that TP53-induced glycolysis and apoptosis regulator (TIGAR) has been attributed to the regulation of metabolic pathways and neuroprotective effect. In the present study, we showed in a mouse model that 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) caused lysosomal damage and DA neurons loss in the SNpc. MPTP only induced SP1-mediated TIGAR upregulation in the early stage of neurotoxin-induced pathology, and this compensatory mechanism was not enough to maintain normal lysosomal function. MPTP significantly decreased the levels of NADPH and GSH, and the effects were ameliorated by the expression of exogenous TIGAR but execerbated by knockdown of TIAGR. TIGAR or NADPH alleviated oxidative stress, rescued lysosomal dysfunction and attenuated DA neurons degeneration. Overexpression of TIGAR or NADPH supplement inhibited MPP+-mediated reactive oxygen species (ROS), lysosomal membrane permeabilization (LMP) and autophagic flux impairment in PC12 cells. Together, these findings suggest that TIGAR reduces MPTP-mediated oxidative stress, lysosomal depletion and DA neuron damage.

中文翻译：

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TP53 诱导的糖酵解和细胞凋亡调节剂 (TIGAR) 改善 1-methyl-4-phenyl-1, 2, 3, 6-四氢吡啶介导的帕金森病小鼠模型中的溶酶体损伤

黑质致密部 (SNpc) 中多巴胺能 (DA) 神经元的逐渐丧失与帕金森病 (PD) 中溶酶体的破裂相关。已经发现TP53诱导的糖酵解和细胞凋亡调节剂（TIGAR）被归因于代谢途径的调节和神经保护作用。在本研究中，我们在小鼠模型中显示 1-methyl-4-phenyl-1, 2, 3, 6-四氢吡啶 (MPTP) 导致 SNpc 中的溶酶体损伤和 DA 神经元丢失。MPTP 仅在神经毒素诱导病理的早期阶段诱导 SP1 介导的 TIGAR 上调，这种补偿机制不足以维持正常的溶酶体功能。MPTP 显着降低 NADPH 和 GSH 的水平，外源性 TIGAR 的表达改善了这种作用，但 TIAGR 的敲低会加剧这种作用。TIGAR 或 NADPH 可减轻氧化应激，挽救溶酶体功能障碍并减轻 DA 神经元变性。TIGAR 或 NADPH 补充剂的过度表达抑制了 MPP+ 介导的活性氧 (ROS)、溶酶体膜透化 (LMP) 和 PC12 细胞中的自噬通量受损。总之，这些发现表明 TIGAR 减少了 MPTP 介导的氧化应激、溶酶体耗竭和 DA 神经元损伤。