title: Induced pluripotent stem cell models from X-linked adrenoleukodystrophy patients.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Department of Physiology, Brain Korea 21 Project for Medical Science and Severance Biomedical Science Institute, Seoul, Korea.
authors: Jiho
authors: J
authors: Jang
authors: Hoon-Chul
authors: HC
authors: Kang
authors: Han-Soo
authors: HS
authors: Kim
authors: Ji Young
authors: JY
authors: Kim
authors: Yong Jun
authors: YJ
authors: Huh
authors: Dae-Sung
authors: DS
authors: Kim
authors: Jeong-Eun
authors: JE
authors: Yoo
authors: Jeong-Ah
authors: JA
authors: Lee
authors: Boyoung
authors: B
authors: Lim
authors: Jiwon
authors: J
authors: Lee
authors: Tae-Min
authors: TM
authors: Yoon
authors: In-Hyun
authors: IH
authors: Park
authors: Dong-Youn
authors: DY
authors: Hwang
authors: George Q
authors: GQ
authors: Daley
authors: Dong-Wook
authors: DW
authors: Kim
mesh_terms: D000074061:ATP Binding Cassette Transporter, Subfamily D; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000326:Adrenoleukodystrophy / Q000378:metabolism / Q000473:pathology*; D001921:Brain / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D004247:DNA / Q000235:genetics; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000473:pathology*; D008148:Lovastatin / Q000494:pharmacology; D009474:Neurons / Q000473:pathology; D009836:Oligodendroglia / Q000473:pathology; D010641:Phenotype; D010654:Phenylbutyrates / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C431694:ABCD2 protein, human; D000074061:ATP Binding Cassette Transporter, Subfamily D; D018528:ATP-Binding Cassette Transporters; D005230:Fatty Acids, Nonesterified; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010654:Phenylbutyrates; C075773:4-phenylbutyric acid; D004247:DNA; D008148:Lovastatin