Induced pluripotent stem cell models from X-linked adrenoleukodystrophy patients
Open accessAbstract
Objective: Because of a lack of an appropriate animal model system and the inaccessibility of human oligodendrocytes in vivo, X‐linked adrenoleukodystrophy (X‐ALD)‐induced pluripotent stem cells (iPSCs) would provide a unique cellular model for studying etiopathophysiology and development of therapeutics for X‐ALD. Methods: We generated and characterized iPSCs of the 2 major types of X‐ALD, childhood cerebral ALD (CCALD) and adrenomyeloneuropathy (AMN), and differentiated them into oligodendrocytes and neurons. We evaluated disease‐relevant phenotypes by pharmacological and genetic approaches. Results: We established iPSCs from the patients with CCALD and AMN. Both CCALD and AMN iPSCs normally differentiated into oligodendrocytes, the cell type primarily affected in the X‐ALD brain, indicating no developmental defect due to the ABCD1 mutations. Although low in X‐ALD iPSCs, very long chain fatty acid (VLCFA) level was significantly increased after oligodendrocyte differentiation. VLCFA accumulation was much higher in CCALD oligodendrocytes than AMN oligodendrocytes but was not significantly different between CCALD and AMN neurons, indicating that the severe clinical manifestations in CCALD might be associated with abnormal VLCFA accumulation in oligodendrocytes. Furthermore, the abnormal accumulation of VLCFA in the X‐ALD oligodendrocytes can be reduced by the upregulated ABCD2 gene expression after treatment with lovastatin or 4‐phenylbutyrate. Interpretation: X‐ALD iPSC model recapitulates the key events of disease development (ie, VLCFA accumulation in oligodendrocytes), provides new clues for better understanding of the disease, and allows for early and accurate diagnosis of the disease subtypes. X‐ALD oligodendrocytes can be a useful cell model system to develop new therapeutics for treating X‐ALD. ANN NEUROL 2011;
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AMN patient-specific iPSC-derived OLs showed normal VLCFA levels in a third study.
“as well as normal VLCFA levels in a third study [479].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [479]
Elevated VLCFA levels in iPSCs from cALD patients were found in another study.
“whereas elevated VLCFA levels in iPSCs from cALD patients were found in another study [479].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [479]
Cites
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“A recent introduction to iPSC technology opened a new avenue not only for cell replacement therapy,(29) but also for disease modeling.(30) In this study, we successfully generated iPSC lines from fibroblasts of patients with 2 major subtypes of X-ALD, the most severe, CCALD, and late onset AMN, and differentiated them…”
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- Authors
- Jang, J., Kang, H., Kim, H., Kim, J. Y., Huh, Y. J., Kim, D., Yoo, J., Lee, J., Lim, B., Lee, J., Yoon, T., Park, I., Hwang, D., Daley, G. Q., & Kim, D.
- Affiliations
- Yonsei University (KR)
- CHA University (KR)
- Boston Children's Hospital (US)
- Corresponding author
- Kim, Dong‐Wook
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2011-06-30
- Volume
- 70
- Issue
- 3
- Pages
- 402-409
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- OpenAlex
- W2095718298
- Cited by
- 109
- References
- 10
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 3 · 2023: 3 · 2022: 4 · 2021: 2 · 2020: 6 · 2019: 4 · 2018: 5 · 2017: 6 · 2016: 10 · 2015: 10 · 2014: 10 · 2013: 14 · 2012: 20
- FWCI
- 9.45
- Type
- journal article
- Language
- en
- Open access
- Licence
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- X-linked adrenoleukodystrophy, induced pluripotent stem cells, oligodendrocytes, very long chain fatty acids, ABCD1 mutations, ABCD2, childhood cerebral adrenoleukodystrophy, adrenomyeloneuropathy, iPSC differentiation, lovastatin, 4-phenylbutyric acid, disease modeling
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily D, Adrenoleukodystrophy, Brain, Cell Differentiation, DNA, Fatty Acids, Nonesterified, Humans, Lovastatin, Neurons, Oligodendroglia, Phenotype, Phenylbutyrates, Hematopoietic Stem Cell Transplantation, ATP-Binding Cassette Transporters, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Excitatory Postsynaptic Potentials, Reverse Transcriptase Polymerase Chain Reaction, Induced Pluripotent Stem Cells
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