Smandzich Nadine J, Pich Andreas, Gschwendtberger Thomas, Greten Stephan, Ye Lan, Klietz Martin, Di Fonzo Alessio, Henkel Lisa M, Wegner Florian
Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.
Center for Systems Neuroscience Hannover (ZSN), 30625 Hannover, Germany.
Cells. 2025 Sep 6;14(17):1394. doi: 10.3390/cells14171394.
The rare and rapidly progressive neurodegenerative disease multiple system atrophy (MSA) mainly affects the striatum and other subcortical brain regions. In this atypical Parkinsonian syndrome, the protein alpha-synuclein aggregates and misfolds in neurons as well as glial cells and is released in elevated amounts by hypoexcitable neurons. Mitochondrial dysregulation affects the biosynthesis of coenzyme Q10 and the activity of the respiratory chain, as shown in an induced pluripotent stem cell (iPSC) model. Proteome studies of cerebrospinal fluid and brain tissue from MSA patients yielded inconsistent results regarding possible protein changes due to small and combined groups of atypical Parkinsonian syndromes. In this study, we analysed the cellular proteome of MSA patient-derived striatal GABAergic medium spiny neurons. We observed 25 significantly upregulated and 16 significantly downregulated proteins in MSA cell lines compared to matched healthy controls. Various protein types involved in diverse molecular functions and cellular processes emphasise the multifaceted pathomechanisms of MSA. These data could contribute to the development of novel disease-modifying treatment strategies for MSA patients.
罕见且进展迅速的神经退行性疾病多系统萎缩（MSA）主要影响纹状体及其他大脑皮质下区域。在这种非典型帕金森综合征中，蛋白质α-突触核蛋白在神经元以及神经胶质细胞中聚集并错误折叠，且由兴奋性不足的神经元大量释放。线粒体功能失调影响辅酶Q10的生物合成及呼吸链的活性，这在诱导多能干细胞（iPSC）模型中得到了证实。由于非典型帕金森综合征的病例数量少且合并在一起，针对MSA患者脑脊液和脑组织的蛋白质组研究在可能的蛋白质变化方面得出了不一致的结果。在本研究中，我们分析了源自MSA患者的纹状体γ-氨基丁酸能中型多棘神经元的细胞蛋白质组。与匹配的健康对照相比，我们在MSA细胞系中观察到25种蛋白质显著上调，16种蛋白质显著下调。涉及多种分子功能和细胞过程的各种蛋白质类型强调了MSA多方面的发病机制。这些数据可能有助于为MSA患者开发新的疾病修饰治疗策略。
