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Induced pluripotent stem cell models from X-linked adrenoleukodystrophy patients

 Jiho Jang  ;  Hoon-Chul Kang  ;  Han-Soo Kim  ;  Ji Young Kim  ;  Yong Jun Huh  ;  Dae-Sung Kim  ;  Jeong-Eun Yoo  ;  Jeong-Ah Lee  ;  Boyoung Lim  ;  Jiwon Lee  ;  Tae-Min Yoon  ;  In-Hyun Park  ;  Dong-Youn Hwang  ;  George Q. Daley  ;  Dong-Wook Kim 
 ANNALS OF NEUROLOGY, Vol.70(3) : 402-409, 2011 
Journal Title
Issue Date
ATP Binding Cassette Transporter, Sub-Family D ; ATP-Binding Cassette Transporters/genetics ; Adrenoleukodystrophy/metabolism ; Adrenoleukodystrophy/pathology* ; Brain/pathology ; CellDifferentiation/drug effects ; CellDifferentiation/physiology ; DNA/genetics ; Excitatory Postsynaptic Potentials/drug effects ; Fatty Acids, Nonesterified/metabolism ; HematopoieticStemCellTransplantation ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology ; Induced Pluripotent Stem Cells/metabolism ; Induced Pluripotent Stem Cells/pathology* ; Lovastatin/pharmacology ; Neurons/pathology ; Oligodendroglia/pathology ; Phenotype ; Phenylbutyrates/pharmacology ; Reverse Transcriptase Polymerase Chain Reaction
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.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Laboratory Medicine (진단검사의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pediatrics (소아과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Physiology (생리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
Yonsei Authors
Kang, Hoon Chul(강훈철) ORCID logo https://orcid.org/0000-0002-3659-8847
Kim, Dae Sung(김대성)
Kim, Dong Wook(김동욱) ORCID logo https://orcid.org/0000-0002-5025-1532
Kim, Ji Young(김지영)
Kim, Han Soo(김한수)
Yoo, Jeong Eun(유정은) ORCID logo https://orcid.org/0000-0001-9990-279X
Lee, Jeong Ah(이정아)
Lee, Ji Won(이지원)
Lim, Bo Young(임보영)
Jang, Ji Ho(장지호) ORCID logo https://orcid.org/0000-0001-5551-3514
Huh, Yong Jun(허용준)
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