Induced pluripotent stem cell models from X-linked adrenoleukodystrophy patients

Jiho Jang, hoonchul 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

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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. 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;

Original languageEnglish
Pages (from-to)402-409
Number of pages8
JournalAnnals of Neurology
Volume70
Issue number3
DOIs
Publication statusPublished - 2011 Sep 1

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Adrenoleukodystrophy
Induced Pluripotent Stem Cells
Oligodendroglia
Fatty Acids
Neurons
Lovastatin

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology

Cite this

Jang, J., kang, H., Kim, H. S., Kim, J. Y., Huh, Y. J., Kim, D. S., ... Kim, D. W. (2011). Induced pluripotent stem cell models from X-linked adrenoleukodystrophy patients. Annals of Neurology, 70(3), 402-409. https://doi.org/10.1002/ana.22486
Jang, Jiho ; kang, hoonchul ; Kim, Han Soo ; Kim, Ji Young ; Huh, Yong Jun ; Kim, Dae Sung ; Yoo, Jeong Eun ; Lee, Jeong Ah ; Lim, Boyoung ; Lee, Jiwon ; Yoon, Tae Min ; Park, In Hyun ; Hwang, Dong Youn ; Daley, George Q. ; Kim, Dong Wook. / Induced pluripotent stem cell models from X-linked adrenoleukodystrophy patients. In: Annals of Neurology. 2011 ; Vol. 70, No. 3. pp. 402-409.
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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. 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;",
author = "Jiho Jang and hoonchul kang and Kim, {Han Soo} and Kim, {Ji Young} and Huh, {Yong Jun} and Kim, {Dae Sung} and Yoo, {Jeong Eun} and Lee, {Jeong Ah} and Boyoung Lim and Jiwon Lee and Yoon, {Tae Min} and Park, {In Hyun} and Hwang, {Dong Youn} and Daley, {George Q.} and Kim, {Dong Wook}",
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Jang, J, kang, H, Kim, HS, Kim, JY, Huh, YJ, Kim, DS, Yoo, JE, Lee, JA, Lim, B, Lee, J, Yoon, TM, Park, IH, Hwang, DY, Daley, GQ & Kim, DW 2011, 'Induced pluripotent stem cell models from X-linked adrenoleukodystrophy patients', Annals of Neurology, vol. 70, no. 3, pp. 402-409. https://doi.org/10.1002/ana.22486

Induced pluripotent stem cell models from X-linked adrenoleukodystrophy patients. / Jang, Jiho; kang, hoonchul; Kim, Han Soo; Kim, Ji Young; Huh, Yong Jun; Kim, Dae Sung; Yoo, Jeong Eun; Lee, Jeong Ah; Lim, Boyoung; Lee, Jiwon; Yoon, Tae Min; Park, In Hyun; Hwang, Dong Youn; Daley, George Q.; Kim, Dong Wook.

In: Annals of Neurology, Vol. 70, No. 3, 01.09.2011, p. 402-409.

Research output: Contribution to journalArticle

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T1 - Induced pluripotent stem cell models from X-linked adrenoleukodystrophy patients

AU - Jang, Jiho

AU - kang, hoonchul

AU - Kim, Han Soo

AU - Kim, Ji Young

AU - Huh, Yong Jun

AU - Kim, Dae Sung

AU - Yoo, Jeong Eun

AU - Lee, Jeong Ah

AU - Lim, Boyoung

AU - Lee, Jiwon

AU - Yoon, Tae Min

AU - Park, In Hyun

AU - Hwang, Dong Youn

AU - Daley, George Q.

AU - Kim, Dong Wook

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N2 - 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;

AB - 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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