Evolution of the lipidome uncovers early changes in adrenoleukodystrophy human cortical and spinal organoids
Summary
Lipids are critical for the structure, signaling, and metabolism of the central nervous system (CNS), yet their roles during human brain development remain underexplored due to limited tissue availability. X-linked adrenoleukodystrophy (ALD), a peroxisomal disorder caused by ABCD1 mutations, disrupts very long-chain fatty acid (VLCFA) degradation, leading to axonal degeneration and demyelination. To investigate lipid dynamics in CNS development and ALD pathogenesis, we generated human induced pluripotent stem cell (hiPSC)-derived cortical and spinal cord organoids and performed lipidomics over 200 days. Lipidomic analysis revealed a dynamic lipidome, with changes in lipid abundance, saturation, and chain length reflecting neurodevelopment. ALD hiPSC-derived organoids exhibited significant lipid alterations over time, including elevated VLCFA levels and reductions in brain-relevant lipids, such as sulfatides and gangliosides, in cortical organoids. These findings provide a foundational resource for studying lipid dynamics in CNS development and emphasize the value of organoids for understanding ALD and other CNS diseases. © 2025 The Author(s).
| Authors | Ferrer RM, Jaspers YRJ, Coveña N, Breeuwsma N, Dijkstra IME, Kempff J, Klinken JV, Wortel J, van Weering JRT, Engelen M, Kemp S, Heine VM |
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| Journal | iScience |
| Publication Date | 2026 Jan 16;29(1):114339 |
| PubMed | 41509916 |
| PubMed Central | PMC12774698 |
| DOI | 10.1016/j.isci.2025.114339 |