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

## TL;DR

This study uses brain-like organoids to track lipid changes during human brain development and reveals early lipid abnormalities in a genetic disorder called adrenoleukodystrophy.

## Contribution

The study introduces a novel use of lipidomics in human organoids to uncover early lipid dysregulation in adrenoleukodystrophy.

## Key findings

- ALD organoids show early and persistent buildup of very long-chain fatty acids
- Organoid lipid changes mirror those seen in ALD patient brain tissue
- Lipidomic analysis reveals dynamic lipid changes during human cortical and spinal organoid development

## 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.

•Lipidomics shows dynamic lipid changes in human cortical and spinal organoids•ALD organoids show early and persistent buildup of very long-chain fatty acids•Organoid lipid changes mirror those seen in ALD patient brain tissue•Organoids enable the study of neurodevelopmental lipid dysregulation in ALD

Lipidomics shows dynamic lipid changes in human cortical and spinal organoids

ALD organoids show early and persistent buildup of very long-chain fatty acids

Organoid lipid changes mirror those seen in ALD patient brain tissue

Organoids enable the study of neurodevelopmental lipid dysregulation in ALD

Nervous system anatomy; Developmental neuroscience; Lipidomics