英国健康老龄化研究所Adrian M. Isaacs研究团队揭示了神经元多不饱和脂肪酸对ALS/FTD具有保护作用。该项研究成果发表在2025年2月25日出版的《自然—神经科学》上。

在这里，该课题组报告了C9orf72重复扩增果蝇模型中脂肪酸和脂质代谢基因表达减少的保守转录组特征，C9orf72重复扩增是肌萎缩性侧索硬化症和额颞叶痴呆（ALS/FTD）最常见的遗传基因，以及人类死后ALS脊髓。该课题组人员对C9 ALS/FTD果蝇、诱导多能干细胞（iPS）神经元和死后FTD脑组织进行了脂质组学研究。这揭示了含有多不饱和脂肪酸（PUFAs）的磷脂种类的共同和特异性减少。喂食C9 ALS/FTD果蝇PUFAs可适度提高存活率。

然而，通过过度表达脂肪酸去饱和酶，增加C9 ALS/FTD果蝇神经元中PUFA水平，导致寿命大幅延长。在C9和TDP-43 ALS/FTD患者的iPS细胞神经元中，脂肪酸去饱和酶的神经元过表达也抑制了应激源诱导的神经元死亡。这些数据暗示神经元脂肪酸饱和与ALS/FTD的发病机制有关，并提示增加神经元PUFA水平的干预可能是有益的。

附：英文原文

Title: Neuronal polyunsaturated fatty acids are protective in ALS/FTD

Author: Giblin, Ashling, Cammack, Alexander J., Blomberg, Niek, Anoar, Sharifah, Mikheenko, Alla, Carcol, Mireia, Atilano, Magda L., Hull, Alex, Shen, Dunxin, Wei, Xiaoya, Coneys, Rachel, Zhou, Lele, Mohammed, Yassene, Olivier-Jimenez, Damien, Wang, Lian Y., Kinghorn, Kerri J., Niccoli, Teresa, Coyne, Alyssa N., van der Kant, Rik, Lashley, Tammaryn, Giera, Martin, Partridge, Linda, Isaacs, Adrian M.

Issue&Volume: 2025-02-25

Abstract: Here we report a conserved transcriptomic signature of reduced fatty acid and lipid metabolism gene expression in a Drosophila model of C9orf72 repeat expansion, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), and in human postmortem ALS spinal cord. We performed lipidomics on C9 ALS/FTD Drosophila, induced pluripotent stem (iPS) cell neurons and postmortem FTD brain tissue. This revealed a common and specific reduction in phospholipid species containing polyunsaturated fatty acids (PUFAs). Feeding C9 ALS/FTD flies PUFAs yielded a modest increase in survival. However, increasing PUFA levels specifically in neurons of C9 ALS/FTD flies, by overexpressing fatty acid desaturase enzymes, led to a substantial extension of lifespan. Neuronal overexpression of fatty acid desaturases also suppressed stressor-induced neuronal death in iPS cell neurons of patients with both C9 and TDP-43 ALS/FTD. These data implicate neuronal fatty acid saturation in the pathogenesis of ALS/FTD and suggest that interventions to increase neuronal PUFA levels may be beneficial.

DOI: 10.1038/s41593-025-01889-3

Source: https://www.nature.com/articles/s41593-025-01889-3