The DDHD2-STXBP1 interaction mediates long-term memory via generation of saturated free fatty acids.

Autor:	Akefe IO; Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, St Lucia, QLD, 4072, Australia.; Academy for Medical Education, Medical School, The University of Queensland, 288 Herston Road, 4006, Brisbane, QLD, Australia., Saber SH; Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, St Lucia, QLD, 4072, Australia.; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, St Lucia, QLD, 4072, Australia., Matthews B; Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, St Lucia, QLD, 4072, Australia., Venkatesh BG; Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, St Lucia, QLD, 4072, Australia., Gormal RS; Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, St Lucia, QLD, 4072, Australia., Blackmore DG; Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, St Lucia, QLD, 4072, Australia., Alexander S; Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, St Lucia, QLD, 4072, Australia., Sieriecki E; School of Medical Science, University of New South Wales, Randwick, NSW, 2052, Australia.; EMBL Australia, Single Molecule Node, University of New South Wales, Sydney, 2052, Australia., Gambin Y; School of Medical Science, University of New South Wales, Randwick, NSW, 2052, Australia.; EMBL Australia, Single Molecule Node, University of New South Wales, Sydney, 2052, Australia., Bertran-Gonzalez J; Decision Neuroscience Lab, School of Psychology, UNSW Sydney, Sydney, Australia., Vitale N; Institut des Neurosciences Cellulaires et Intégratives, UPR-3212 CNRS - Université de Strasbourg, Strasbourg, France., Humeau Y; Interdisciplinary Institute for Neuroscience, CNRS UMR 5297, Université de Bordeaux, Bordeaux, France., Gaudin A; Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, St Lucia, QLD, 4072, Australia., Ellis SA; Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, St Lucia, QLD, 4072, Australia., Michaels AA; Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA.; The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, USA., Xue M; Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA.; The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Cravatt B; The Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA., Joensuu M; Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, St Lucia, QLD, 4072, Australia. m.joensuu@uq.edu.au.; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, St Lucia, QLD, 4072, Australia. m.joensuu@uq.edu.au., Wallis TP; Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, St Lucia, QLD, 4072, Australia. t.wallis@uq.edu.au., Meunier FA; Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, St Lucia, QLD, 4072, Australia. f.meunier@uq.edu.au.; The School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, 4072, Australia. f.meunier@uq.edu.au.
Jazyk:	angličtina
Zdroj:	The EMBO journal [EMBO J] 2024 Feb; Vol. 43 (4), pp. 533-567. Date of Electronic Publication: 2024 Feb 05.
DOI:	10.1038/s44318-024-00030-7
Abstrakt:	The phospholipid and free fatty acid (FFA) composition of neuronal membranes plays a crucial role in learning and memory, but the mechanisms through which neuronal activity affects the brain's lipid landscape remain largely unexplored. The levels of saturated FFAs, particularly of myristic acid (C14:0), strongly increase during neuronal stimulation and memory acquisition, suggesting the involvement of phospholipase A1 (PLA1) activity in synaptic plasticity. Here, we show that genetic ablation of the PLA1 isoform DDHD2 in mice dramatically reduces saturated FFA responses to memory acquisition across the brain. Furthermore, DDHD2 loss also decreases memory performance in reward-based learning and spatial memory models prior to the development of neuromuscular deficits that mirror human spastic paraplegia. Via pulldown-mass spectrometry analyses, we find that DDHD2 binds to the key synaptic protein STXBP1. Using STXBP1/2 knockout neurosecretory cells and a haploinsufficient STXBP1 +/- mouse model of human early infantile encephalopathy associated with intellectual disability and motor dysfunction, we show that STXBP1 controls targeting of DDHD2 to the plasma membrane and generation of saturated FFAs in the brain. These findings suggest key roles for DDHD2 and STXBP1 in lipid metabolism and in the processes of synaptic plasticity, learning, and memory. (© 2024. The Author(s).)
Databáze:	MEDLINE
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