Gu Rou, Bai Liping, Yan Fang, Zhang Se, Zhang Xianwen, Deng Ruhua, Zeng Xiansi, Sun Bo, Hu Xiaomei, Li Ye, Bai Jie
Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, China.
Laboratory of Molecular Neurobiology, Medical School, Kunming University of Science and Technology, Kunming, China.
Cell Death Discov. 2024 Feb 22;10(1):93. doi: 10.1038/s41420-024-01848-0.
Parkinson's disease (PD) is characterized by the formation of Lewy body in dopaminergic neurons in the substantia nigra pars compacta (SNpc). Alpha-synuclein (α-syn) is a major component of Lewy body. Autophagy eliminates damaged organelles and abnormal aggregated proteins. Thioredoxin-1 (Trx-1) is a redox regulating protein and plays roles in protecting dopaminergic neurons against neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). However, the relationship between Trx-1 and α-syn in PD is still unknown. In the present study, the movement disorder and dopaminergic neurotoxicity in MPTP-treated mice were improved by Trx-1 overexpression and were aggravated by Trx-1 knockdown in the SNpc in mice. The expression of α-syn was increased in the SNpc of MPTP-treated mice, which was inhibited by Trx-1 overexpression and was exacerbated in Trx-1 knockdown mice. Autophagosomes was increased under electron microscope after MPTP treatment, which were recovered in Trx-1 overexpressing mice and were further increased in Trx-1 knockdown in the SNpc in mice. The expressions of phosphatase and tensin homolog deleted on chromosome ten (PTEN)-induced putative kinase 1 (PINK1), Parkin, LC3 II and p62 were increased by MPTP, which were blocked in Trx-1 overexpressing mice and were further increased in Trx-1 knockdown mice. Cathepsin D was decreased by MPTP, which was restored in Trx-1 overexpressing mice and was further decreased in Trx-1 knockdown mice. The mRFP-GFP-LC3 green fluorescent dots were increased by 1-methyl-4-phenylpyridinium (MPP) and further increased in Trx-1 siRNA transfected PC12 cells, while mRFP-GFP-LC3 red fluorescent dots were increased in Trx-1 overexpressing cells. These results indicate that Trx-1 may eliminate α-syn in PD mice through potentiating autophagy-lysosome pathway.
帕金森病（PD）的特征是黑质致密部（SNpc）中多巴胺能神经元内路易小体的形成。α-突触核蛋白（α-syn）是路易小体的主要成分。自噬可清除受损细胞器和异常聚集的蛋白质。硫氧还蛋白-1（Trx-1）是一种氧化还原调节蛋白，在保护多巴胺能神经元免受1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的神经毒性中发挥作用。然而，PD中Trx-1与α-syn之间的关系仍不清楚。在本研究中，Trx-1过表达改善了MPTP处理小鼠的运动障碍和多巴胺能神经毒性，而在小鼠SNpc中敲低Trx-1则使其加重。MPTP处理小鼠的SNpc中α-syn的表达增加，Trx-1过表达抑制了该增加，而在Trx-1敲低小鼠中则加剧。MPTP处理后电镜下自噬体增加，在Trx-1过表达小鼠中恢复，而在小鼠SNpc中敲低Trx-1后进一步增加。MPTP增加了第10号染色体缺失的磷酸酶和张力蛋白同源物（PTEN）诱导的推定激酶1（PINK1）、帕金、微管相关蛋白轻链3 II（LC3 II）和p62的表达，在Trx-1过表达小鼠中被阻断，而在Trx-1敲低小鼠中进一步增加。MPTP使组织蛋白酶D减少，在Trx-1过表达小鼠中恢复，而在Trx-1敲低小鼠中进一步减少。1-甲基-4-苯基吡啶鎓（MPP）增加了mRFP-GFP-LC3绿色荧光点，在Trx-1小干扰RNA转染的PC12细胞中进一步增加，而mRFP-GFP-LC3红色荧光点在Trx-1过表达细胞中增加。这些结果表明，Trx-1可能通过增强自噬-溶酶体途径清除PD小鼠中的α-syn。
