Evolution of the lipidome uncovers early changes in adrenoleukodystrophy human cortical and spinal organoids

Roberto Montoro Ferrer; Yorrick R.J. Jaspers; Nicki Coveña; Nicole Breeuwsma; Inge M.E. Dijkstra; Julia Kempff; Jan Bert van Klinken; Joke Wortel; Jan R.T. van Weering; Marc Engelen; Stephan Kemp; Vivi M. Heine

doi:10.1016/j.isci.2025.114339

Evolution of the lipidome uncovers early changes in adrenoleukodystrophy human cortical and spinal organoids

Roberto Montoro Ferrer
, Yorrick R.J. Jaspers
, Nicki Coveña
, Nicole Breeuwsma
, Inge M.E. Dijkstra
, Julia Kempff
, Jan Bert van Klinken
, Joke Wortel
, Jan R.T. van Weering
, Marc Engelen
, Stephan Kemp
, Vivi M. Heine^*

^*Corresponding author for this work

University of Amsterdam
University of Amsterdam
Vrije Universiteit Amsterdam

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

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.

Original language	English
Article number	114339
Journal	iScience
Volume	29
Issue number	1
DOIs	https://doi.org/10.1016/j.isci.2025.114339
Publication status	Published - 16 Jan 2026

Keywords

Developmental neuroscience
Lipidomics
Nervous system anatomy

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Ferrer, R. M., Jaspers, Y. R. J., Coveña, N., Breeuwsma, N., Dijkstra, I. M. E., Kempff, J., Klinken, J. B. V., Wortel, J., van Weering, J. R. T., Engelen, M., Kemp, S., & Heine, V. M. (2026). Evolution of the lipidome uncovers early changes in adrenoleukodystrophy human cortical and spinal organoids. iScience, 29(1), Article 114339. https://doi.org/10.1016/j.isci.2025.114339

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title = "Evolution of the lipidome uncovers early changes in adrenoleukodystrophy human cortical and spinal organoids",

abstract = "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.",

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AU - Ferrer, Roberto Montoro

AU - Jaspers, Yorrick R.J.

AU - Coveña, Nicki

AU - Breeuwsma, Nicole

AU - Dijkstra, Inge M.E.

AU - Kempff, Julia

AU - Klinken, Jan Bert van

AU - Wortel, Joke

AU - van Weering, Jan R.T.

AU - Engelen, Marc

AU - Kemp, Stephan

AU - Heine, Vivi M.

PY - 2026/1/16

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N2 - 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.

AB - 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.

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KW - Lipidomics

KW - Nervous system anatomy

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Evolution of the lipidome uncovers early changes in adrenoleukodystrophy human cortical and spinal organoids

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