Zhang Xianwen, Yan Fang, He Xiong Jie, Chen Yali, Gu Rou, Dong Xianghuan, Wei Yonghang, Bai Liping, Bai Jie
Medical Faculty, Laboratory of Molecular Neurobiology, Kunming University of Science and Technology, Kunming, China.
Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, China.
Antioxid Redox Signal. 2025 Jul;43(1-3):138-150. doi: 10.1089/ars.2024.0630. Epub 2025 Mar 26.
Parkinson's disease (PD) is characterized by dopaminergic (DAergic) neuron degeneration in the substantia nigra pars compacta (SNpc). Thioredoxin-1 (Trx-1) is a redox protein that protects neurons from various injuries. Our study revealed that Trx-1 overexpression improved the learning and memory impairments induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). However, the role of the specific transmission of signals from the SNpc to the hippocampus regulated by Trx-1 in cognition deficits associated with PD is still unknown. We observed that Trx-1 downregulation in the SNpc aggravated cognitive dysfunction induced by MPTP. Importantly, we observed that the SNpc directly projects to the hippocampus. We found that the loss of DAergic neurons in the SNpc induced by MPTP resulted in a decrease in dopamine D1 receptor (D1R) expression in the hippocampus, which was promoted by Trx-1 downregulation in the SNpc. The levels of phosphorylated extracellular signal-regulated kinase (p-ERK1/2), phosphorylated cAMP-response element binding protein (p-CREB), brain-derived neurotrophic factor (BDNF), and postsynaptic density protein 95 (PSD95) in the hippocampus were decreased by MPTP and further decreased by Trx-1 downregulation in the SNpc. Finally, the number of synapses in the hippocampus was decreased by MPTP in the hippocampus and further reduced by Trx-1 downregulation in the SNpc. Trx-1 downregulation accelerated the loss of DAergic neurons in the SNpc, leading to a decrease in the number dopaminergic projections to the hippocampus, subsequently inhibiting the D1R-ERK1/2-CREB-BDNF pathway in the hippocampus, and ultimately impairing hippocampus-dependent cognition. These results indicate that a decrease in Trx-1 level in the SNpc plays a critical regulatory role in cognitive dysfunction in individuals with PD by decreasing the hippocampal D1R signaling pathway. 43, 138-150.
帕金森病（PD）的特征是黑质致密部（SNpc）中的多巴胺能（DAergic）神经元变性。硫氧还蛋白-1（Trx-1）是一种氧化还原蛋白，可保护神经元免受各种损伤。我们的研究表明，Trx-1过表达改善了由1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的学习和记忆障碍。然而，由Trx-1调节的从SNpc到海马体的特定信号传递在与PD相关的认知缺陷中的作用仍然未知。我们观察到，SNpc中Trx-1的下调加剧了MPTP诱导的认知功能障碍。重要的是，我们观察到SNpc直接投射到海马体。我们发现，MPTP诱导的SNpc中DAergic神经元的丧失导致海马体中多巴胺D1受体（D1R）表达的降低，而SNpc中Trx-1的下调促进了这种降低。MPTP降低了海马体中磷酸化细胞外信号调节激酶（p-ERK1/2）、磷酸化环磷酸腺苷反应元件结合蛋白（p-CREB）、脑源性神经营养因子（BDNF）和突触后致密蛋白95（PSD95）的水平，而SNpc中Trx-1的下调进一步降低了这些水平。最后，MPTP减少了海马体中的突触数量，而SNpc中Trx-1的下调进一步减少了突触数量。Trx-1的下调加速了SNpc中DAergic神经元的丧失，导致投射到海马体的多巴胺能神经纤维数量减少，随后抑制了海马体中的D1R-ERK1/2-CREB-BDNF通路，并最终损害了海马体依赖性认知。这些结果表明，SNpc中Trx-1水平的降低通过降低海马体D1R信号通路在PD患者的认知功能障碍中起关键调节作用。43, 138 - 150。
