Basırlı Hande, Ateş Nurselin, Seyrantepe Volkan
Department of Molecular Biology and Genetics, Izmir Institute of Technology, Gulbahce Mah, Urla, 35430, Izmir, Turkey.
Izmir Institute of Technology, IYTEDEHAM, Urla, 35430, Izmir, Turkey.
Mol Biol Rep. 2025 Mar 5;52(1):282. doi: 10.1007/s11033-025-10380-y.
Tay-Sachs disease is a neurodegenerative disorder characterized by a build-up of GM2 ganglioside in the brain, which results in progressive central nervous system dysfunction. Our group recently generated Hexa-/-Neu3-/- mice, a murine model with neuropathological abnormalities similar to the infantile form of Tay-Sachs disease. Previously, we reported progressive neurodegeneration with neuronal loss in the brain sections of Hexa-/-Neu3-/- mice. However, the relationship between the severity of neurodegeneration and the imbalance in redox homeostasis was not yet clarified in Hexa-/-Neu3-/- mice. Here, we evaluated whether neurodegeneration is associated with oxidative stress in the tissues and cells of Hexa-/-Neu3-/- mice and neuroglia cells from Tay-Sachs patients.
Cell death and oxidative stress-related markers were evaluated in four brain regions and fibroblasts of 5-month-old WT, Hexa-/-, Neu3-/-, and Hexa-/-Neu3-/- mice and human neuroglia cells using Western blot, RT-PCR, and immunohistochemistry analyses. We further analyzed oxidative stress levels in the samples using flow cytometry analyses. We discovered neuronal death, alterations in intracellular ROS levels, and damaging effects of oxidative stress, especially in the cerebellum and fibroblasts of Hexa-/-Neu3-/- mice.
Our results showed that alteration in redox homeostasis might be related to neurodegeneration in the murine model of Tay-Sachs Disease. These findings suggest that targeting the altered redox balance and increased oxidative stress might be a rational therapeutic approach for alleviating neurodegeneration and treating Tay-Sachs disease.
泰-萨克斯病是一种神经退行性疾病，其特征是大脑中GM2神经节苷脂蓄积，导致进行性中枢神经系统功能障碍。我们的研究小组最近培育出了Hexa-/-Neu3-/-小鼠，这是一种神经病理学异常与婴儿型泰-萨克斯病相似的小鼠模型。此前，我们报道了Hexa-/-Neu3-/-小鼠脑切片中存在进行性神经退行性变并伴有神经元丢失。然而，在Hexa-/-Neu3-/-小鼠中，神经退行性变的严重程度与氧化还原稳态失衡之间的关系尚未阐明。在此，我们评估了神经退行性变是否与Hexa-/-Neu3-/-小鼠以及泰-萨克斯病患者的神经胶质细胞的组织和细胞中的氧化应激有关。
使用蛋白质免疫印迹法、逆转录-聚合酶链反应和免疫组织化学分析，对5月龄野生型、Hexa-/-、Neu3-/-和Hexa-/-Neu3-/-小鼠的四个脑区和成纤维细胞以及人类神经胶质细胞中的细胞死亡和氧化应激相关标志物进行了评估。我们还使用流式细胞术分析进一步检测了样本中的氧化应激水平。我们发现神经元死亡、细胞内活性氧水平改变以及氧化应激的损伤作用，尤其是在Hexa-/-Neu3-/-小鼠的小脑和成纤维细胞中。
我们的结果表明，氧化还原稳态的改变可能与泰-萨克斯病小鼠模型中的神经退行性变有关。这些发现表明，针对氧化还原平衡改变和氧化应激增加进行干预可能是缓解神经退行性变和治疗泰-萨克斯病的合理治疗方法。
