Department of Life Science, Kyonggi University, Suwon, South Korea.
Department of Neurology, College of Medicine, Yonsei University, Seoul, South Korea.
Brain Res. 2025 Jan 1;1846:149250. doi: 10.1016/j.brainres.2024.149250. Epub 2024 Sep 21.
This study delineated the intricate relation between cholesterol metabolism, protein degradation mechanisms, and the pathogenesis of Huntington's disease (HD). Through investigations using both animal models and cellular systems, we have observed significant alterations in cholesterol levels, particularly in the striatum, which is the primary lesion site in HD. Our findings indicate the dysregulation of cholesterol metabolism-related factors, such as LDLR and SREBP2, in HD, which may contribute to disease progression. Additionally, we uncovered disruptions in protein degradation pathways, including decreased neddylated proteins and dysregulated autophagy, which further exacerbated HD pathology. Moreover, our study highlighted the potential therapeutic implications of targeting these pathways. By restoring cholesterol levels and modulating protein degradation mechanisms, particularly through interventions, such as MLN4924, we observed potential improvements in cellular function, as indicated by the increased BDNF levels. These insights underscore the importance of simultaneously addressing cholesterol metabolism and protein degradation to alleviate HD pathology. Collectively, this study provides a basic understanding of the interplay between the decrease of SREBP2 and the dysfunctional protein degradation system derived from disrupted cholesterol metabolism in HD and HD cells.
本研究描绘了胆固醇代谢、蛋白质降解机制与亨廷顿病（HD）发病机制之间的复杂关系。通过使用动物模型和细胞系统进行的研究，我们观察到胆固醇水平的显著变化，特别是在纹状体，这是 HD 的主要病变部位。我们的研究结果表明，在 HD 中存在与胆固醇代谢相关的因子（如 LDLR 和 SREBP2）的失调，这可能导致疾病进展。此外，我们还发现了蛋白质降解途径的破坏，包括去泛素化蛋白减少和自噬失调，这进一步加重了 HD 的病理学。此外，我们的研究强调了靶向这些途径的潜在治疗意义。通过恢复胆固醇水平和调节蛋白质降解机制，特别是通过干预，如 MLN4924，我们观察到细胞功能的潜在改善，这表现为 BDNF 水平的增加。这些发现突显了同时解决胆固醇代谢和蛋白质降解以减轻 HD 病理学的重要性。总之，本研究提供了对 HD 中 SREBP2 减少和源自胆固醇代谢紊乱的功能失调蛋白质降解系统之间相互作用的基本理解。
