Department of Neurosciences, Experimental Neurology, Leuven Brain Institute, KU Leuven-University of Leuven, 3000 Leuven, Belgium.
Center for Brain & Disease Research, Laboratory of Neurobiology, VIB, 3000 Leuven, Belgium.
Int J Mol Sci. 2021 Oct 18;22(20):11224. doi: 10.3390/ijms222011224.
Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disorder of the motor system. While the etiology is still incompletely understood, defects in metabolism act as a major contributor to the disease progression. Recently, histone deacetylase (HDAC) inhibition using ACY-738 has been shown to restore metabolic alterations in the spinal cord of a FUS mouse model of ALS, which was accompanied by a beneficial effect on the motor phenotype and survival. In this study, we investigated the specific effects of HDAC inhibition on lipid metabolism using untargeted lipidomic analysis combined with transcriptomic analysis in the spinal cord of FUS mice. We discovered that symptomatic FUS mice recapitulate lipid alterations found in ALS patients and in the SOD1 mouse model. Glycerophospholipids, sphingolipids, and cholesterol esters were most affected. Strikingly, HDAC inhibition mitigated lipid homeostasis defects by selectively targeting glycerophospholipid metabolism and reducing cholesteryl esters accumulation. Therefore, our data suggest that HDAC inhibition is a potential new therapeutic strategy to modulate lipid metabolism defects in ALS and potentially other neurodegenerative diseases.
肌萎缩侧索硬化症（ALS）是一种不可治愈的致命运动系统神经退行性疾病。虽然其病因仍不完全清楚，但代谢缺陷是疾病进展的主要原因。最近，使用ACY-738 抑制组蛋白去乙酰化酶（HDAC）已被证明可恢复 ALS FUS 小鼠模型脊髓中的代谢异常，这伴随着对运动表型和生存的有益影响。在这项研究中，我们使用非靶向脂质组学分析结合脊髓转录组学分析，研究了 HDAC 抑制对脂质代谢的具体影响在 FUS 小鼠中。我们发现，有症状的 FUS 小鼠重现了在 ALS 患者和 SOD1 小鼠模型中发现的脂质改变。甘油磷脂、鞘脂和胆固醇酯受影响最大。令人惊讶的是，HDAC 抑制通过选择性靶向甘油磷脂代谢和减少胆固醇酯积累来缓解脂质动态平衡缺陷。因此，我们的数据表明，HDAC 抑制是一种潜在的新治疗策略，可调节 ALS 及潜在其他神经退行性疾病中的脂质代谢缺陷。
