Liu Jin, Liu Yi, Gao Chao, Pan Hong, Huang Pei, Tan Yuyan, Chen Shengdi
Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
Department of Neurology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
Aging Cell. 2025 Apr;24(4):e14436. doi: 10.1111/acel.14436. Epub 2024 Nov 29.
Recent studies indicated that the dysregulation of mitochondria-associated endoplasmic reticulum membrane (MAM) could be a significant hub in the pathogenesis of Parkinson's disease (PD). However, little has been known about how MAM altered in PD. This study was aimed to observe morphological changes and analyze proteomic profiles of MAM in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse models. In MPTP-treated mice, transmission electron microscopy was applied for MAM ultrastructural visualization. Nano ultra-high performance liquid chromatography-tandem mass spectrum and bioinformatic analysis were adopted to obtain underlying molecular data of MAM fractions. The loosened, shortened and reduced MAM tethering was found in substantia nigral neurons from MPTP-treated mice. In midbrain MAM proteomics, 158 differentially expressed proteins (DEPs) were identified between two groups. Specific DEPs were validated by western blot and exhibited significantly statistical changes, aligning with proteomic results. Bioinformatic analysis indicated that membrane, cytoplasm and cell projection were three major localizations for DEPs. Biological processes including metabolism, lipid transport, and immunological and apoptotic signaling pathways were greatly affected. For consensus MAM proteins, the enriched pathway analysis revealed the potential relationship between neurodegenerative diseases and MAM. Several biological processes such as peroxisome function and clathrin-mediated endocytosis, were clustered, which provided additional insights into the fundamental molecular pathways associated with MAM. In our study, we demonstrated disrupted ER-mitochondria contacts in an MPTP-induced PD mouse model. The underlying signatures of MAM were revealed by proteomics and bioinformatic analysis, providing valuable insights into its potential role in PD pathogenesis.
最近的研究表明，线粒体相关内质网膜（MAM）的失调可能是帕金森病（PD）发病机制中的一个重要枢纽。然而，关于MAM在PD中如何改变却知之甚少。本研究旨在观察1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的PD小鼠模型中MAM的形态变化并分析其蛋白质组学特征。在MPTP处理的小鼠中，应用透射电子显微镜对MAM进行超微结构观察。采用纳米超高效液相色谱-串联质谱和生物信息学分析来获取MAM组分的潜在分子数据。在MPTP处理小鼠的黑质神经元中发现MAM连接松弛、缩短且数量减少。在中脑MAM蛋白质组学中，两组之间鉴定出158种差异表达蛋白（DEP）。通过蛋白质免疫印迹法验证了特定的DEP，其显示出显著的统计学变化，与蛋白质组学结果一致。生物信息学分析表明，膜、细胞质和细胞突起是DEP的三个主要定位。包括代谢、脂质转运以及免疫和凋亡信号通路在内的生物学过程受到极大影响。对于共有MAM蛋白，富集通路分析揭示了神经退行性疾病与MAM之间的潜在关系。几个生物学过程，如过氧化物酶体功能和网格蛋白介导的内吞作用，被聚类，这为与MAM相关的基本分子途径提供了更多见解。在我们的研究中，我们在MPTP诱导的PD小鼠模型中证明了内质网-线粒体接触的破坏。通过蛋白质组学和生物信息学分析揭示了MAM的潜在特征，为其在PD发病机制中的潜在作用提供了有价值的见解。
