Detection of Characteristic Phosphatidylcholine Containing Very Long Chain Fatty Acids in Cerebrospinal Fluid from Patients with X-Linked Adrenoleukodystrophy

Fujitani, Naoki; Saito, Masayoshi; Akashi, Tomoya; Morita, Masashi; So, Takanori; Oka, Koichi

doi:10.1248/bpb.b22-00506

Cited by 2 publications

(4 citation statements)

References 16 publications

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“…We have shown that the presence of VLCFA-containing PCs, such as PC 44:4 (24:0/20:4) and PC 46:4 (26:0/20:4), in the CSF is characteristic of patients with X-ALD. 6 Consistently, PC 44:4 (24:0/20:4) and PC 46:4 (26:0/20:4) were significantly increased in HDL secreted from Abcd1-deficient astrocytes (pink letter in Figure 4D, E and Table 1). These findings suggest that increased PC 44:4 (24:0/20:4) and PC 46:4 (26:0/20:4) content in the CSF of patients with X-ALD could be derived from HDL secreted from astrocytes.…”

Section: Discussionsupporting

confidence: 53%

“…Therefore, apoE‐containing HDL secreted from astrocytes may play a central role in maintaining phospholipid levels in the CSF. We have shown that the presence of VLCFA‐containing PCs, such as PC 44:4 (24:0/20:4) and PC 46:4 (26:0/20:4), in the CSF is characteristic of patients with X‐ALD 6 . Consistently, PC 44:4 (24:0/20:4) and PC 46:4 (26:0/20:4) were significantly increased in HDL secreted from Abcd1 ‐deficient astrocytes (pink letter in Figure 4D, E and Table 1).…”

Section: Discussionmentioning

confidence: 98%

“…Moreover, LysoPC 26:0 levels have been demonstrated to be a superior diagnostic marker for ALD compared with VLCFA analysis (C26:0 and C26:0/C22:0) 4 . We have shown that the presence of VLCFA‐containing phosphatidylcholine (PC), such as PC 44:4 (24:0/20:4) and PC 46:4 (26:0/20:4), in the cerebrospinal fluid (CSF) is characteristic of patients with X‐ALD 6 . The abnormal accumulation of VLCFA in the central nervous system (CNS) could be the pathological basis of X‐ALD 3,7 .…”

Section: Introductionmentioning

confidence: 99%

“…4 We have shown that the presence of VLCFA-containing phosphatidylcholine (PC), such as PC 44:4 (24:0/20:4) and PC 46:4 (26:0/20:4), in the cerebrospinal fluid (CSF) is characteristic of patients with X-ALD. 6 The abnormal accumulation of VLCFA in the central nervous system (CNS) could be the pathological basis of X-ALD. 3,7 Activated astrocytes have been detected in CNS in autopsy samples from patients with X-ALD.…”

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confidence: 99%

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Increased neurotoxicity of high‐density lipoprotein secreted from murine reactive astrocytes deficient in a peroxisomal very‐long‐chain fatty acid transporter Abcd1

Fujitani,

Akashi,

Saito

et al. 2023

J of Inher Metab Disea

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X‐linked adrenoleukodystrophy (X‐ALD) is a genetic neurodegenerative disorder caused by pathogenic variants in ABCD1, resulting in the accumulation of very‐long‐chain fatty acids (VLCFAs) in tissues. The etiology of X‐ALD is unclear. Activated astrocytes play a pathological role in X‐ALD. Recently, reactive astrocytes have been shown to induce neuronal cell death via saturated lipids in high‐density lipoprotein (HDL), although how HDL from reactive astrocytes exhibits neurotoxic effects has yet to be determined. In this study, we obtained astrocytes from wild‐type and Abcd1‐deficient mice. HDL was purified from the culture supernatant of astrocytes, and the effect of HDL on neurons was evaluated in vitro. To our knowledge, this study shows for the first time that HDL obtained from Abcd1‐deficient reactive astrocytes induces a significantly higher level of lactate dehydrogenase (LDH) release, a marker of cell damage, from mouse primary cortical neurons as compared to HDL from wild‐type reactive astrocytes. Notably, HDL from Abcd1‐deficient astrocytes contained significantly high amounts of VLCFA‐containing phosphatidylcholine (PC) and LysoPC. Activation of Abcd1‐deficient astrocytes led to the production of HDL containing decreased amounts of PC with arachidonic acid in sn‐2 acyl moieties and increased amounts of LysoPC, presumably through cytosolic phospholipase A2α upregulation. These results suggest that compositional changes in PC and LysoPC in HDL, due to Abcd1 deficiency and astrocyte activation, may contribute to neuronal damage. Our findings provide novel insights into central nervous system pathology in X‐ALD.

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Increased neurotoxicity of high‐density lipoprotein secreted from murine reactive astrocytes deficient in a peroxisomal very‐long‐chain fatty acid transporter Abcd1

Fujitani,

Akashi,

Saito

et al. 2023

J of Inher Metab Disea

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Imbalanced mitochondrial dynamics contributes to the pathogenesis of X-linked adrenoleukodystrophy

Launay,

Lopez-Erauskin,

Bianchi

et al. 2024

Brain

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The peroxisomal disease adrenoleukodystrophy (X-ALD) is caused by loss of the transporter of very-long-chain fatty acids (VLCFAs), ABCD1. An excess of VLCFAs disrupts essential homeostatic functions crucial for axonal maintenance, including redox metabolism, glycolysis and mitochondrial respiration. As mitochondrial function and morphology are intertwined, we set out to investigate the role of mitochondrial dynamics in X-ALD models. Using quantitative 3D transmission electron microscopy, we revealed mitochondrial fragmentation in corticospinal axons in Abcd1− mice. In patient fibroblasts, an excess of VLCFAs triggers mitochondrial fragmentation through the redox-dependent phosphorylation of DRP1 (DRP1S616). The blockade of DRP1-driven fission by the peptide P110 effectively preserved mitochondrial morphology. Furthermore, mRNA inhibition of DRP1 not only prevented mitochondrial fragmentation but also protected axonal health in a Caenorhabditis elegans model of X-ALD, underscoring DRP1 as a potential therapeutic target. Elevated levels of circulating cell-free mtDNA in patients’ CSF align this leukodystrophy with primary mitochondrial disorders. Our findings underscore the intricate interplay between peroxisomal dysfunction, mitochondrial dynamics and axonal integrity in X-ALD, shedding light on potential avenues for therapeutic intervention.

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Detection of Characteristic Phosphatidylcholine Containing Very Long Chain Fatty Acids in Cerebrospinal Fluid from Patients with X-Linked Adrenoleukodystrophy

Cited by 2 publications

References 16 publications

Increased neurotoxicity of high‐density lipoprotein secreted from murine reactive astrocytes deficient in a peroxisomal very‐long‐chain fatty acid transporter Abcd1

Increased neurotoxicity of high‐density lipoprotein secreted from murine reactive astrocytes deficient in a peroxisomal very‐long‐chain fatty acid transporter Abcd1

Imbalanced mitochondrial dynamics contributes to the pathogenesis of X-linked adrenoleukodystrophy

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