Alterations in lipid metabolism of spinal cord linked to amyotrophic lateral sclerosis
Alterations in lipid metabolism of spinal cord linked to amyotrophic lateral sclerosis
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DOI：
10.1038/s41598-019-48059-7
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发表时间：
2019-08-12
影响因子：
4.6
通讯作者：
Miyamoto, Sayuri
中科院分区：
文献类型：
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作者：
Chaves-Filho, Adriano Britto;Dantas Pinto, Isabella Fernanda;Miyamoto, Sayuri
肌萎缩侧索硬化症（ALS）的特征在于上、下运动神经元的进行性丧失，导致肌肉麻痹和死亡。虽然已经提出了脂质代谢失调和ALS之间的联系，但涉及疾病进展的脂质组改变仍然研究不足。使用ALS过表达突变型人Cu/Zn-超氧化物歧化酶基因（SOD 1-G93 A）的啮齿动物模型，我们在无症状（类似于70天）和有症状阶段（类似于120天）对SOD 1-G93 A和WT大鼠的运动皮层和脊髓组织进行了比较脂质组学分析。有趣的是，运动皮质中脂质体的改变与年龄的相关性大于ALS。与此相反，在SOD 1-G93 A 120 d组的脊髓中观察到剧烈的变化，包括心磷脂水平降低和与多不饱和脂肪酸连接的几种胆固醇酯增加6倍。与以前的研究一致，我们的研究结果表明运动神经元中的线粒体异常和异常星形胶质细胞中的脂滴积聚。虽然导致胆固醇酯积累的机制仍有待建立，我们假设一个假设的模型的基础上，神经保护的多不饱和脂肪酸进入脂滴在增加氧化应激。与其他神经退行性疾病的病理学有关，胆固醇酯似乎是进一步研究的有吸引力的目标。
Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of upper and lower motor neurons leading to muscle paralysis and death. While a link between dysregulated lipid metabolism and ALS has been proposed, lipidome alterations involved in disease progression are still understudied. Using a rodent model of ALS overexpressing mutant human Cu/Zn-superoxide dismutase gene (SOD1-G93A), we performed a comparative lipidomic analysis in motor cortex and spinal cord tissues of SOD1-G93A and WT rats at asymptomatic (similar to 70 days) and symptomatic stages (similar to 120 days). Interestingly, lipidome alterations in motor cortex were mostly related to age than ALS. In contrast, drastic changes were observed in spinal cord of SOD1-G93A 120d group, including decreased levels of cardiolipin and a 6-fold increase in several cholesteryl esters linked to polyunsaturated fatty acids. Consistent with previous studies, our findings suggest abnormal mitochondria in motor neurons and lipid droplets accumulation in aberrant astrocytes. Although the mechanism leading to cholesteryl esters accumulation remains to be established, we postulate a hypothetical model based on neuroprotection of polyunsaturated fatty acids into lipid droplets in response to increased oxidative stress. Implicated in the pathology of other neurodegenerative diseases, cholesteryl esters appear as attractive targets for further investigations.