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Functional genomic analysis unravels a metabolic-inflammatory interplay in adrenoleukodystrophy

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Schlüter, Agatha, Espinosa, Lluís, Fourcade, Stéphane, Galino, Jorge, López, Eva, Ilieva, Ekaterina, Morató, Laia, Asheuer, Muriel +8 more·2012·Human Molecular Genetics
DOI 10.1093/hmg/ddr536PMC PMC3277307
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Abstract

X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder characterized by axonopathy and demyelination in the central nervous system and adrenal insufficiency. Main X-ALD phenotypes are: (i) an adult adrenomyeloneuropathy (AMN) with axonopathy in spinal cords, (ii) cerebral AMN with brain demyelination (cAMN) and (iii) a childhood variant, cALD, characterized by severe cerebral demyelination. Loss of function of the ABCD1 peroxisomal fatty acid transporter and subsequent accumulation of very-long-chain fatty acids (VLCFAs) are the common culprits to all forms of X-ALD, an aberrant microglial activation accounts for the cerebral forms, whereas inflammation allegedly plays no role in AMN. How VLCFA accumulation leads to neurodegeneration and what factors account for the dissimilar clinical outcomes and prognosis of X-ALD variants remain elusive. To gain insights into these questions, we undertook a transcriptomic approach followed by a functional-enrichment analysis in spinal cords of the animal model of AMN, the Abcd1(-) null mice, and in normal-appearing white matter of cAMN and cALD patients. We report that the mouse model shares with cAMN and cALD a common signature comprising dysregulation of oxidative phosphorylation, adipocytokine and insulin signaling pathways, and protein synthesis. Functional validation by quantitative polymerase chain reaction, western blots and assays in spinal cord organotypic cultures confirmed the interplay of these pathways through IkB kinase, being VLCFA in excess a causal, upstream trigger promoting the altered signature. We conclude that X-ALD is, in all its variants, a metabolic/inflammatory syndrome, which may offer new targets in X-ALD therapeutics.

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  • Experimental results from A. Pujol's laboratory demonstrated overproduction of redox free radicals altering mitochondrial functions in brain white matter or cultured cells.

    “Experimental results from A. Pujol’s laboratory demonstrated overproduction of redox free radicals altering mitochondrial functions in brain white matter or cultured cells [80,136,179,180,181,182,183,184,185,186,187,188,189].”

    From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [80]

    The Results section, “Oxidative stress underlying disease progression,” reports oxidative-stress signatures and mitochondrial-gene dysregulation in mouse spinal cords, but describes mitochondrial dysfunction as predicted. The Discussion, “VLCFAs cause oxidative stress and mitochondrial dysregulation,” reports oxidative damage and impaired energy metabolism in patient fibroblasts; its evidence for damage in human brains is attributed to other studies. Thus the paper supports the oxidative and metabolic findings in cultured cells, but not a direct demonstration here that excess radicals altered mitochondrial function in brain white matter. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Electron microscopy reveals characteristic cytoplasmic inclusions (spicules) in oligodendrocytes, perivascular macrophages, and/or microglia but not in astrocytes.

    “Electron microscopy reveals characteristic cytoplasmic inclusions (“spicules”) in OLs, perivascular macrophages, and/or microglia but not in astrocytes.”

    From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [80]

    The Introduction discusses inflammatory pathology in cerebral ALD, and Materials and Methods (Human brain samples) describes staining brain sections, but neither reports electron microscopy or cytoplasmic spicules. Searches for “spicules” and for electron-microscopy inclusions in the named cell types found no passage addressing the claim; page numbers were unavailable in our copy. (LLM, conf=0.76)

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References 60 · Cited by 72

Research works printed but not linked: 46

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Authors
Schlüter, A., Espinosa, L., Fourcade, S., Galino, J., López, E., Ilieva, E., Morató, L., Asheuer, M., Cook, T., McLaren, A., Reid, J., Kelly, F., Bates, S., Aubourg, P., Galea, E., & Pujol, A.
Affiliations
  • Institut d'Investigació Biomédica de Bellvitge (ES)
  • Inserm (FR)
  • Institució Catalana de Recerca i Estudis Avançats (ES)
Corresponding author
Pujol, Aurora
ORCID
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2011-11-17
Volume
21
Issue
5
Pages
1062-1077
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
DOI
10.1093/hmg/ddr536
PMC
PMC3277307
OpenAlex
W2147955643
Cited by
72
References
60
Citations by year
2025: 5 · 2024: 2 · 2023: 2 · 2022: 8 · 2021: 6 · 2020: 2 · 2019: 3 · 2018: 4 · 2017: 5 · 2016: 1 · 2015: 7 · 2014: 7 · 2013: 13 · 2012: 6
FWCI
5.01
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Human Molecular Genetics (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • European Commission (241622)
  • Association Européenne contre les Leucodystrophies
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
Keywords
X-linked adrenoleukodystrophy, ABCD1, very long chain fatty acids, adrenomyeloneuropathy, cerebral adrenoleukodystrophy, demyelination, oxidative phosphorylation, adipocytokine signaling, insulin signaling, protein synthesis, IκB kinase, microglial activation, neuroinflammation, spinal cord transcriptome, white matter
MeSH terms
ATP Binding Cassette Transporter, Subfamily D, Member 1, Adrenoleukodystrophy, Adult, Animals, Brain, Child, Disease Models, Animal, Fatty Acids, Humans, Insulin, Insulin Resistance, Oxidative Phosphorylation, Spinal Cord, Signal Transduction, Gene Expression, NF-kappa B, Oxidative Stress, Disease Progression, ATP-Binding Cassette Transporters, Leptin, Gene Expression Profiling, Toll-Like Receptors, Mice, I-kappa B Kinase, Adiponectin, Metabolic Networks and Pathways, Biosynthetic Pathways, Adipokines, Genetic Association Studies, Transcriptome

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