Ferrer Roberto Montoro, Jaspers Yorrick R J, Dijkstra Inge M E, Breeuwsma Nicole, van Klinken Jan-Bert, Romero Cato, Engelen Marc, Kemp Stephan, Heine Vivi M
Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam UMC, Amsterdam Gastroenterology Endocrinology Metabolism, University of Amsterdam, Amsterdam, The Netherlands.
Department of Pediatric Neurology, Emma Children's Hospital, Amsterdam UMC, Amsterdam Leukodystrophy Center, Amsterdam Neuroscience, University of Amsterdam, Amsterdam, The Netherlands.
J Inherit Metab Dis. 2025 Jan;48(1):e12832. doi: 10.1002/jimd.12832.
X-linked adrenoleukodystrophy (ALD) is a peroxisomal disorder resulting from pathogenic variants in the ABCD1 gene that primarily affects the nervous system and is characterized by progressive axonal degeneration in the spinal cord and peripheral nerves and leukodystrophy. Dysfunction of peroxisomal very long-chain fatty acid (VLCFA) degradation has been implicated in ALD pathology, but the impact on astrocytes, which critically support neuronal function, remains poorly understood. Fibroblasts from four ALD patients were reprogrammed to generate human-induced pluripotent stem cells (hiPSC). hiPSC-derived astrocytes were generated to study the impact of ALD on astrocytic fatty acid homeostasis. Our study reveals significant changes in the lipidome of ALD hiPSC-derived astrocytes, characterized by an enrichment of VLCFAs across multiple lipid classes, including triacylglycerols, cholesteryl esters, and phosphatidylcholines. Importantly, ALD hiPSC-derived astrocytes not only exhibit intrinsic lipid dysregulation but also affect the dendritic tree complexity of neurons in co-culture systems. These findings highlight the cell-autonomous effects of pathogenic variants in the ABCD1 protein on astrocytes and their microenvironment, shed light on potential mechanisms underlying ALD neuropathology, and underscore the critical role of astrocytes in neuronal health.
X连锁肾上腺脑白质营养不良（ALD）是一种过氧化物酶体疾病，由ABCD1基因的致病变异引起，主要影响神经系统，其特征为脊髓和周围神经的进行性轴突变性以及脑白质营养不良。过氧化物酶体极长链脂肪酸（VLCFA）降解功能障碍与ALD病理相关，但对至关重要地支持神经元功能的星形胶质细胞的影响仍知之甚少。对4名ALD患者的成纤维细胞进行重编程以生成人诱导多能干细胞（hiPSC）。生成hiPSC来源的星形胶质细胞以研究ALD对星形胶质细胞脂肪酸稳态的影响。我们的研究揭示了ALD hiPSC来源的星形胶质细胞脂质组的显著变化，其特征是多种脂质类别（包括三酰甘油、胆固醇酯和磷脂酰胆碱）中VLCFA的富集。重要的是，ALD hiPSC来源的星形胶质细胞不仅表现出内在的脂质失调，而且还会影响共培养系统中神经元的树突复杂性。这些发现突出了ABCD1蛋白中的致病变异对星形胶质细胞及其微环境的细胞自主效应，揭示了ALD神经病理学的潜在机制，并强调了星形胶质细胞在神经元健康中的关键作用。
