2025
EMBO J . 2025 Jun 17. doi: 10.1038/s44318-025-00484-3. Online ahead of print.
Lysine myristoylation mediates long-term potentiation via membrane enrichment of synaptic plasticity effectors
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. The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia. Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, St Lucia, QLD, 4072, Australia. Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, St Lucia, QLD, 4072, Australia. The School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, 4072, Australia.
Service type: Stock strains
Abstract
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.
Keywords: N-Myristoyl Transferase; DDHD2; Long-Term Potentiation; Lysine Myristoylation; Myristic Acid.
