IRCCS Neuromed, Via Dell'elettronica, 86077 Pozzilli, Italy.
Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy.
Int J Mol Sci. 2023 Mar 22;24(6):5956. doi: 10.3390/ijms24065956.
Huntington's disease is one of the most common dominantly inherited neurodegenerative disorders caused by an expansion of a polyglutamine (polyQ) stretch in the N-terminal region of huntingtin (Htt). Among all the molecular mechanisms, affected by the mutation, emerging evidence proposes glycosphingolipid dysfunction as one of the major determinants. High levels of sphingolipids have been found to localize in the myelin sheaths of oligodendrocytes, where they play an important role in myelination stability and functions. In this study, we investigated any potential existing link between sphingolipid modulation and myelin structure by performing both ultrastructural and biochemical analyses. Our findings demonstrated that the treatment with the glycosphingolipid modulator THI preserved myelin thickness and the overall structure and reduced both area and diameter of pathologically giant axons in the striatum of HD mice. These ultrastructural findings were associated with restoration of different myelin marker protein, such as myelin-associated glycoprotein (MAG), myelin basic protein (MBP) and 2', 3' Cyclic Nucleotide 3'-Phosphodiesterase (CNP). Interestingly, the compound modulated the expression of glycosphingolipid biosynthetic enzymes and increased levels of GM1, whose elevation has been extensively reported to be associated with reduced toxicity of mutant Htt in different HD pre-clinical models. Our study further supports the evidence that the metabolism of glycosphingolipids may represent an effective therapeutic target for the disease.
亨廷顿病是最常见的常染色体显性遗传神经退行性疾病之一，由亨廷顿蛋白（Htt）N 端区域的多聚谷氨酰胺（polyQ）延伸引起。在所有受突变影响的分子机制中，越来越多的证据表明糖脂代谢功能障碍是主要决定因素之一。研究发现，鞘脂类物质大量定位于少突胶质细胞的髓鞘中，在髓鞘稳定性和功能中发挥重要作用。在这项研究中，我们通过进行超微结构和生化分析，研究了糖脂代谢调节与髓鞘结构之间可能存在的联系。研究结果表明，糖脂代谢调节剂 THI 的治疗维持了 HD 小鼠纹状体髓鞘的厚度和整体结构，并减少了病理性巨轴突的面积和直径。这些超微结构发现与不同髓鞘标记蛋白的恢复有关，如髓鞘相关糖蛋白（MAG）、髓鞘碱性蛋白（MBP）和 2',3'环核苷酸 3'-磷酸二酯酶（CNP）。有趣的是，该化合物调节糖脂生物合成酶的表达，并增加 GM1 的水平，GM1 的升高已被广泛报道与不同 HD 临床前模型中突变型 Htt 毒性降低有关。我们的研究进一步支持了糖脂代谢可能是该疾病有效治疗靶点的证据。
