Matthews Benjamin, Steeves Sevannah A, Akefe Isaac O, Ahmed Noorya Yasmin, Gormal Rachel S, Dehorter Nathalie, Wallis Tristan P, Meunier Frédéric A
Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, St Lucia, QLD, 4072, Australia.
CDU Menzies School of Medicine, Charles Darwin University, Ellengowan Drive, Darwin, NT, 0909, Australia.
EMBO J. 2025 Jun 17. doi: 10.1038/s44318-025-00484-3.
Synaptic plasticity underlying long-term memory is associated with the generation of saturated free fatty acids (sFFAs) -particularly myristic acid- from membrane phospholipids by the phospholipase A1 isoform DDHD2. However, the mechanism through which myristic acid contributes to synaptic plasticity remains elusive. Here we demonstrate that DDHD2-derived myristic acid is rapidly converted to myristoyl CoA, which serves as the substrate for N-myristoyl transferases (NMT1/2), to promote post-translational lysine myristoylation of synaptic proteins. Chemically-induced long-term potentiation (cLTP) in cortical neurons increases both sFFAs and their CoA-conjugates, predominantly myristoyl CoA, and this response is blocked by the DDHD2 inhibitor KLH-45. KLH-45-mediated inhibition of DDHD2 or IMP-1088-mediated inhibition of NMT1/2 also disrupts cLTP-induced proteomic changes, impairs dendritic spine remodeling, and prevents LTP in hippocampal slices. Instrumental conditioning further induces proteomic changes in the hippocampus, which are abolished in learning-deficient DDHD2 knockout mice. In these mice, key synaptic proteins such as NMDA receptor subunit GluN1, MAP2, and GAS7 fail to undergo learning-induced changes, effectively linking DDHD2 function to learning-dependent proteome remodeling. Our findings reveal that de novo lysine myristoylation promotes synaptic plasticity and memory formation.
长期记忆背后的突触可塑性与磷脂酶A1亚型DDHD2从膜磷脂生成饱和游离脂肪酸（sFFA）——特别是肉豆蔻酸——有关。然而，肉豆蔻酸促进突触可塑性的机制仍不清楚。在这里，我们证明DDHD2衍生的肉豆蔻酸迅速转化为肉豆蔻酰辅酶A，后者作为N-肉豆蔻酰转移酶（NMT1/2）的底物，促进突触蛋白的翻译后赖氨酸肉豆蔻酰化。化学诱导的皮质神经元长期增强（cLTP）增加了sFFA及其辅酶A共轭物，主要是肉豆蔻酰辅酶A，并且这种反应被DDHD2抑制剂KLH-45阻断。KLH-45介导的DDHD2抑制或IMP-1088介导的NMT1/2抑制也会破坏cLTP诱导的蛋白质组变化，损害树突棘重塑，并阻止海马切片中的LTP。工具性条件反射进一步诱导海马体中的蛋白质组变化，这在学习缺陷的DDHD2基因敲除小鼠中被消除。在这些小鼠中，关键的突触蛋白如NMDA受体亚基GluN1、MAP2和GAS7未能发生学习诱导的变化，有效地将DDHD2功能与学习依赖的蛋白质组重塑联系起来。我们的研究结果表明，从头开始的赖氨酸肉豆蔻酰化促进突触可塑性和记忆形成。
