Department of Neurobiology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
SKL of Pharmaceutical Biotechnology and Model Animal Research Center, Collaborative Innovation Center for Genetics and Development, Nanjing Biomedical Research Institute, Nanjing University, Nanjing, 210061, China.
Mol Brain. 2023 Feb 11;16(1):22. doi: 10.1186/s13041-023-01011-3.
Melanoma-associated antigen D1 (Maged1) has critical functions in the central nervous system in both developmental and adult stages. Loss of Maged1 in mice has been linked to depression, cognitive disorder, and drug addiction. However, the role of Maged1 in Parkinson's disease (PD) remains unclear. In this study, we observed that Maged1 was expressed in the dopaminergic (DA) neurons of the substantia nigra in mice and humans, which could be upregulated by the in vivo or in vitro treatment with 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-Methyl-4-phenylpyridinium iodide (MPP). Genetic ablation of Maged1 in mice attenuated motor deficits, the loss of DA neurons, and disease progression induced by MPTP. Moreover, Maged1 deficiency protected DA neurons against MPP-induced toxicity in primary cultured cells. Mechanistically, loss of Maged1 upregulated the Akt signaling pathway and downregulated the mTOR signaling pathway in SH-SY5Y cells, which may in turn attenuate the cell apoptosis and impairment of autophagy. Consistent with it, the degeneration of midbrain and striatum among elderly Maged1 knockout mice was relatively mild compared to those in wild-type mice under physiological conditions. Taken together, this study suggested that Maged1 deficiency inhibited apoptosis and enhanced autophagy, which may provide a new potential target for the therapy of PD.
黑色素瘤相关抗原 D1（Maged1）在中枢神经系统的发育和成年阶段都具有关键功能。在小鼠中缺失 Maged1 与抑郁、认知障碍和药物成瘾有关。然而，Maged1 在帕金森病（PD）中的作用尚不清楚。在这项研究中，我们观察到 Maged1 在小鼠和人类的黑质多巴胺能（DA）神经元中表达，并且可以通过体内或体外用 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）或 1-甲基-4-苯基吡啶碘化物（MPP）处理而上调。在小鼠中敲除 Maged1 可减轻 MPTP 诱导的运动缺陷、DA 神经元丢失和疾病进展。此外，Maged1 缺乏可保护原代培养细胞免受 MPP 诱导的毒性。在机制上，Maged1 缺失可上调 SH-SY5Y 细胞中的 Akt 信号通路并下调 mTOR 信号通路，这可能反过来减轻细胞凋亡和自噬受损。与之一致的是，与野生型小鼠相比，老年 Maged1 敲除小鼠的中脑和纹状体退化在生理条件下相对较轻。总之，这项研究表明，Maged1 缺乏抑制细胞凋亡并增强自噬，这可能为 PD 的治疗提供新的潜在靶点。
