Sadler Gemma L, Lewis Katherine N, Narayana Vinod K, De Souza David P, Mason Joel, McLean Catriona, Gonsalvez David G, Turner Bradley J, Barton Samantha K
Florey Institute of Neuroscience and Mental Health, Melbourne 3052, Australia.
Metabolomics Australia, Bio21 Institute, University of Melbourne, Melbourne 3052, Australia.
Metabolites. 2022 Jun 17;12(6):554. doi: 10.3390/metabo12060554.
Lipid metabolism is profoundly dysregulated in amyotrophic lateral sclerosis (ALS), yet the lipid composition of the white matter, where the myelinated axons of motor neurons are located, remains uncharacterised. We aimed to comprehensively characterise how myelin is altered in ALS by assessing its lipid and protein composition. We isolated white matter from the motor cortex from post-mortem tissue of ALS patients (n = 8 sporadic ALS cases and n = 6 familial ALS cases) and age- and sex-matched controls (n = 8) and conducted targeted lipidomic analyses, qPCR for gene expression of relevant lipid metabolising enzymes and Western blotting for myelin proteins. We also quantified myelin density by using spectral confocal reflectance microscopy (SCoRe). Whilst myelin protein composition was similar in ALS and control tissue, both the lipid levels and the expression of their corresponding enzymes were dysregulated, highlighting altered lipid metabolism in the white matter as well as a likely change in myelin composition. Altered myelin composition could contribute to motor neuron dysfunction, and this highlights how oligodendrocytes may play a critical role in ALS pathogenesis.
脂质代谢在肌萎缩侧索硬化症（ALS）中严重失调，然而运动神经元有髓轴突所在的白质的脂质组成仍未得到表征。我们旨在通过评估髓磷脂的脂质和蛋白质组成，全面表征ALS中髓磷脂的变化情况。我们从ALS患者（8例散发性ALS病例和6例家族性ALS病例）以及年龄和性别匹配的对照者（8例）的死后组织中分离出运动皮层的白质，并进行了靶向脂质组学分析、相关脂质代谢酶基因表达的qPCR以及髓磷脂蛋白的蛋白质印迹分析。我们还使用光谱共聚焦反射显微镜（SCoRe）对髓磷脂密度进行了定量。虽然ALS组织和对照组织中的髓磷脂蛋白质组成相似，但脂质水平及其相应酶的表达均失调，这突出了白质中脂质代谢的改变以及髓磷脂组成可能的变化。髓磷脂组成的改变可能导致运动神经元功能障碍，这突出了少突胶质细胞在ALS发病机制中可能发挥的关键作用。
