ArticleResearch square2026
Acsl4-mediated Lipid Homeostasis Orchestrates Synaptic and Cognitive Plasticity.
Article in Research square, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Authors and funding
15 authors.
Funding
Abstract
Intellectual disability (ID) affects 1-3% of the population, yet effective therapies remain elusive. Dysregulated lipid metabolism has been implicated in ID, but the underlying mechanisms and translational potential are poorly understood. Here, we identify the lipid-metabolizing enzyme acyl-coenzyme A (CoA) synthetase long-chain family member 4 (Acsl4) as a key regulator of synaptic plasticity, engram cell activation, and cognition, in a developmental stage-dependent manner. Neuron-specific Acsl4 knockout mice, which recapitulate key features of human ID, exhibit disrupted diacylglycerol-protein kinase c (PKC) signaling - a pathway essential for memory formation. Lipidomic and transcriptomic profiling reveals a reduction in diacylglycerol species and downregulation of synapse-related genes. Remarkably, restoring expression of the brain-specific Acsl4_B isoform via AAV-mediated gene therapy during development, or pharmacologically activating PKC with Bryostatin 1 - a clinically tested compound - fully rescues cognitive and synaptic deficits. These findings define the pathogenic mechanism of ACSL4-related ID and uncover a therapeutically actionable lipid signaling pathway, providing a framework for targeted intervention in neurodevelopmental disorders involving lipid dysregulation.
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Registered trials
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