Adrenoleukodystrophy (ALD)
https://www.cell.com/iscience/fulltext/S2589-0042(25)02600-8
This study investigates how lipid metabolism changes during early human nervous system development and how these processes are disrupted in the rare genetic disorder X-linked adrenoleukodystrophy (ALD). Lipids are essential molecules in the brain and spinal cord, forming cell membranes, supporting neuronal signalling, and maintaining myelin. ALD is caused by mutations in the ABCD1 gene, which encodes the peroxisomal transporter ALDP which is responsible for importing very-long-chain fatty acids (VLCFAs) into peroxisomes for degradation. To investigate these mechanisms, the researchers of this study generated three-dimensional cortical and spinal cord organoids from human induced pluripotent stem cells (hiPSCs) derived from healthy individuals and patients with ALD. These organoids mimic key aspects of human brain and spinal cord development. Using high-resolution mass spectrometry–based lipidomics, the researchers analysed 2,262 lipid species across 53 lipid subclasses at multiple developmental stages up to 200 days. The results showed that the lipidome (total amount of lipids in cells) of developing organoids is highly dynamic (changes significantly over time). As organoids matured, there was a shift toward longer-chain and more polyunsaturated lipids, along with increasing levels of complex sphingolipids such as sphingomyelin, ceramides, gangliosides, and sulfatides – lipid classes that are critical for neuronal signalling and myelin formation. Organoids derived from individuals with ALD followed a similar developmental trajectory but showed significant biochemical abnormalities. Across all time points, ALD organoids displayed increased VLCFA-containing lipid species, particularly within phosphatidylcholine, triacylglycerol, and cholesteryl ester classes. Importantly, cortical organoids from ALD patients also showed reduced levels of gangliosides and sulfatides, key lipids required for myelin maintenance and axon–glial interactions. These findings suggest that early disruptions in lipid metabolism may contribute to the pathogenesis (disease progression) of ALD and demonstrate the potential of human organoid models to study disease-relevant lipid dysregulation.