Kaya Beyza, Orhan Mehmet Emin, Yanbul Selman, Demirci Müşerref Duygu Saçar, Demir Secil Akyildiz, Seyrantepe Volkan
Department of Molecular Biology and Genetics, İzmir Institute of Technology, İzmir, Turkey.
Department of Bioengineering, Graduate School of Engineering and Science, Abdullah Gül University, Kayseri, Turkey.
J Mol Neurosci. 2025 Aug 9;75(3):103. doi: 10.1007/s12031-025-02395-8.
Tay-Sachs disease (TSD) is a rare lysosomal storage disorder marked by the progressive buildup of GM2 in the central nervous system (CNS). This condition arises from mutations in the HEXA gene, which encodes the α subunit of the enzyme β-hexosaminidase A. A newly developed mouse model for early-onset TSD (Hexa-/-Neu3-/-) exhibited signs of neurodegeneration and neuroinflammation, evidenced by elevated levels of pro-inflammatory cytokines and chemokines, as well as significant astrogliosis and microgliosis. Identifying disease-specific microRNAs (miRNAs) may aid the development of targeted therapies. Although previous small-scale studies have investigated miRNA expression in some regions of GM2 gangliosidosis mouse models, thorough profiling of miRNAs in this innovative TSD model remains to be done. In this study, we employed next-generation sequencing to analyze the complete miRNA profile of neuroglial cells from Hexa-/-Neu3-/- mice. By comparing KEGG and Reactome pathways associated with neurodegeneration, neuroinflammation, and sphingolipid metabolism in Hexa-/-Neu3-/- neuroglial cells, we discovered new microRNAs and their targets related to the pathophysiology of GM2 gangliosidosis. For the first time, our findings showed that miR-708-5p, miR-672-5p, miR-204-5p, miR-335-5p, and miR-296-3p were upregulated, while miR-10 b-5p, miR-615-3p, miR-196a-5p, miR-214-5p, and miR-199a-5p were downregulated in Hexa-/-Neu3-/- neuroglial cells in comparison to age-matched wild-type (WT). These specific changes in miRNA expression deepen our understanding of the disease's neuropathological characteristics in Hexa-/-Neu3-/- mice. Our study suggests that miRNA-based therapeutic strategies may improve clinical outcomes for TSD patients.
泰-萨克斯病（TSD）是一种罕见的溶酶体贮积症，其特征是中枢神经系统（CNS）中GM2逐步蓄积。这种病症源于HEXA基因突变，该基因编码β-己糖胺酶A的α亚基。一种新开发的早发性TSD小鼠模型（Hexa-/-Neu3-/-）表现出神经退行性变和神经炎症的迹象，促炎细胞因子和趋化因子水平升高以及显著的星形胶质细胞增生和小胶质细胞增生证明了这一点。鉴定疾病特异性微小RNA（miRNA）可能有助于开发靶向治疗方法。尽管先前的小规模研究调查了GM2神经节苷脂病小鼠模型某些区域的miRNA表达，但在这个创新的TSD模型中对miRNA进行全面分析仍有待完成。在本研究中，我们采用下一代测序技术分析Hexa-/-Neu3-/-小鼠神经胶质细胞的完整miRNA谱。通过比较Hexa-/-Neu3-/-神经胶质细胞中与神经退行性变、神经炎症和鞘脂代谢相关的KEGG和Reactome通路，我们发现了与GM2神经节苷脂病病理生理学相关的新的微小RNA及其靶标。我们的研究结果首次表明，与年龄匹配的野生型（WT）相比，miR-708-5p、miR-672-5p、miR-204-5p、miR-335-5p和miR-296-3p在Hexa-/-Neu3-/-神经胶质细胞中上调，而miR-10 b-5p、miR-615-3p、miR-196a-5p、miR-214-5p和miR-199a-5p下调。miRNA表达的这些特定变化加深了我们对Hexa-/-Neu3-/-小鼠疾病神经病理学特征的理解。我们的研究表明，基于miRNA的治疗策略可能改善TSD患者的临床结局。
