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Cited by 38Metabolism and Genetic DisordersLysosomal Storage Disorders ResearchPluripotent Stem Cells Research

Functional Characterization of IPSC-Derived Brain Cells as a Model for X-Linked Adrenoleukodystrophy

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Baarine, Mauhamad, Khan, Mushfiquddin, Singh, Avtar, Singh, Inderjit·2015·PLOS ONE
DOI 10.1371/journal.pone.0143238PMC PMC4651558
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Abstract

X-ALD is an inherited neurodegenerative disorder where mutations in the ABCD1 gene result in clinically diverse phenotypes: the fatal disorder of cerebral childhood ALD (cALD) or a milder disorder of adrenomyeloneuropathy (AMN). The various models used to study the pathobiology of X-ALD disease lack the appropriate presentation for different phenotypes of cALD vs AMN. This study demonstrates that induced pluripotent stem cells (IPSC) derived brain cells astrocytes (Ast), neurons and oligodendrocytes (OLs) express morphological and functional activities of the respective brain cell types. The excessive accumulation of saturated VLCFA, a "hallmark" of X-ALD, was observed in both AMN OLs and cALD OLs with higher levels observed in cALD OLs than AMN OLs. The levels of ELOVL1 (ELOVL Fatty Acid Elongase 1) mRNA parallel the VLCFA load in AMN and cALD OLs. Furthermore, cALD Ast expressed higher levels of proinflammatory cytokines than AMN Ast and control Ast with or without stimulation with lipopolysaccharide. These results document that IPSC-derived Ast and OLs from cALD and AMN fibroblasts mimic the respective biochemical disease phenotypes and thus provide an ideal platform to investigate the mechanism of VLCFA load in cALD OLs and VLCFA-induced inflammatory disease mechanisms of cALD Ast and thus for testing of new therapeutics for AMN and cALD disease of X-ALD.

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  • cALD iPSC-derived astrocytes from two patients with cALD expressed higher levels of proinflammatory cytokines than those from two AMN patients and two healthy controls with LPS stimulation or without.

    “cALD iPSC-derived astrocytes from two patients with cALD expressed higher levels of proinflammatory cytokines than those from two AMN patients and two healthy controls with LPS stimulation or without [477].”

    From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [477]

    The Results (Functional characterization of IPSC-derived brain cells; page unavailable) report higher IL-6 and IL-1β mRNA in cALD astrocytes than AMN astrocytes under basal and stimulated conditions. But Materials and Methods (Cell cultures and treatments; page unavailable) identifies one cALD patient and one AMN patient, not two of each; it also lists one healthy donor-derived fibroblast line and a purchased control iPSC line, not two healthy donors. Stimulation used cytokines alone or cytokines plus LPS, not LPS alone. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • AMN patient-specific iPSC-derived OLs showed elevated VLCFA levels compared to healthy controls, but lower levels than those derived from cALD patients in two studies.

    “AMN patient-specific iPSC-derived OLs showed elevated VLCFA levels/, compared to healthy controls, but lower levels than those derived from cALD patients in two studies [477,478]”

    From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [477]

  • Early-passage iPSCs derived from AMN or cALD patients did not have elevated VLCFA levels compared to healthy controls in two studies.

    “At the pluripotent stem cell stage, early-passage iPSCs derived from AMN or cALD patients did not have elevated VLCFA levels compared to healthy controls in two studies [477,478]”

    From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [477]

    The Results section on differential VLCFA accumulation reports measurements in iPSC-derived neurons, oligodendrocytes, and astrocytes, not in early-passage iPSCs at the pluripotent stage. Searches for early-passage and undifferentiated iPSC VLCFA levels found no passage comparing those cells with healthy controls; the finding of unchanged VLCFA in derived neurons does not establish the claim about pluripotent iPSCs. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

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Sorted by citations

Authors
Baarine, M., Khan, M., Singh, A., & Singh, I.
Affiliations
Medical University of South Carolina (US)
Corresponding author
Singh, Inderjit
ORCID
Venue
PLOS ONE
Publisher
Public Library of Science (PLoS)
Published
2015-11-18
Volume
10
Issue
11
Pages
e0143238
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0143238
PMC
PMC4651558
OpenAlex
W2177721564
Cited by
38
References
8
Citations by year
2026: 1 · 2025: 5 · 2024: 8 · 2023: 2 · 2022: 1 · 2021: 4 · 2020: 3 · 2019: 3 · 2018: 4 · 2017: 3 · 2016: 4
FWCI
3.01
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, public-domain)
  • Europe PMC (PubMed Central) (publishedVersion, public-domain)
  • PubMed Central (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (1c06rr015455-01a1, 1c06rr018823-01, NS-22576)
  • National Institute of Neurological Disorders and Stroke (R01NS064195, NS-22576, NS-64195, NS 37766, R01NS037766, R01NS022576, R37NS022576, R01NS072511, NS-72511)
  • National Center for Research Resources (RR 015455, C06 RR-015455, C06 RR, C06 RR-018823)
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, ABCD1 gene, adrenomyeloneuropathy, oligodendrocytes, astrocytes, neurons, very long chain fatty acids, ELOVL1, inflammatory cytokines, lipopolysaccharide, disease modeling, neuroinflammation
MeSH terms
Adrenoleukodystrophy, Adult, Astrocytes, Brain, Cell Differentiation, Child, Fatty Acids, Fibroblasts, Humans, Infant, Newborn, Male, Models, Biological, Neurons, Oligodendroglia, Biomarkers, Case-Control Studies, Induced Pluripotent Stem Cells, Neural Stem Cells

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