AIM Peroxisomes play a key role in lipid metabolism, and peroxisome defects have been associated with neurodegenerative diseases such as X-adrenoleukodystrophy and Alzheimer's disease. The present study aims to elucidate the contribution of peroxisomes in lipid alterations of area 8 of the frontal cortex in the spectrum of TDP43-proteinopathies. Cases of frontotemporal lobar degeneration-TDP43 (FTLD-TDP), manifested as sporadic (sFTLD-TDP) or linked to mutations in various genes including expansions of the non-coding region of C9ORF72 (c9FTLD), and of sporadic amyotrophic lateral sclerosis (sALS) as the most common TDP43 proteinopathies, were analysed. METHODS We used transcriptomics and lipidomics methods to define the steady-state levels of gene expression and lipid profiles. RESULTS Our results show alterations in gene expression of some components of peroxisomes and related lipid pathways in frontal cortex area 8 in sALS, sFTLD-TDP, and c9FTLD. Additionally, we identify a lipidomic pattern associated with the ALS-FTLD-TDP43 proteinopathy spectrum, notably characterized by downregulation of ether lipids and acylcarnitine among other lipid species, as well as alterations in the lipidome of each phenotype of TDP43 proteinopathy, which reveals commonalities and disease-dependent differences in lipid composition. CONCLUSION Globally, lipid alterations in the human frontal cortex of the ALS-FTLD-TDP43 proteinopathy spectrum, which involve cell membrane composition and signalling, vulnerability against cellular stress, and possible glucose metabolism, are partly related to peroxisome impairment.

中文翻译：

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ALS-FTLD-TDP43 蛋白病谱中人类额叶皮层的脂质变化部分与过氧化物酶体损伤有关

AIM 过氧化物酶体在脂质代谢中发挥着关键作用，过氧化物酶体缺陷与 X 肾上腺脑白质营养不良和阿尔茨海默病等神经退行性疾病有关。本研究旨在阐明过氧化物酶体在 TDP43 蛋白病谱中额叶皮层 8 区脂质改变中的作用。额颞叶变性-TDP43 (FTLD-TDP) 病例，表现为散发性 (sFTLD-TDP) 或与多种基因突变相关，包括 C9ORF72 非编码区 (c9FTLD) 的扩展，以及散发性肌萎缩侧索硬化症 (sALS) ）作为最常见的 TDP43 蛋白病，进行了分析。方法我们使用转录组学和脂质组学方法来定义基因表达和脂质谱的稳态水平。结果我们的结果显示，在 sALS、sFTLD-TDP 和 c9FTLD 中，额叶皮层 8 区过氧化物酶体某些成分和相关脂质途径的基因表达发生了变化。此外，我们还确定了与 ALS-FTLD-TDP43 蛋白病谱相关的脂质组学模式，其显着特征是其他脂质种类中醚脂质和酰基肉碱的下调，以及 TDP43 蛋白病每种表型的脂质组的改变，这揭示了共性和脂质成分的疾病依赖性差异。结论 在全球范围内，ALS-FTLD-TDP43 蛋白病谱中人类额叶皮层的脂质改变涉及细胞膜组成和信号传导、细胞应激脆弱性以及可能的葡萄糖代谢，部分与过氧化物酶体损伤有关。