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An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients.
Li, Jonathan; Lim, Ryan G; Kaye, Julia A; Dardov, Victoria; Coyne, Alyssa N; Wu, Jie; Milani, Pamela; Cheng, Andrew; Thompson, Terri G; Ornelas, Loren; Frank, Aaron; Adam, Miriam; Banuelos, Maria G; Casale, Malcolm; Cox, Veerle; Escalante-Chong, Renan; Daigle, J Gavin; Gomez, Emilda; Hayes, Lindsey; Holewenski, Ronald; Lei, Susan; Lenail, Alex; Lima, Leandro; Mandefro, Berhan; Matlock, Andrea; Panther, Lindsay; Patel-Murray, Natasha Leanna; Pham, Jacqueline; Ramamoorthy, Divya; Sachs, Karen; Shelley, Brandon; Stocksdale, Jennifer; Trost, Hannah; Wilhelm, Mark; Venkatraman, Vidya; Wassie, Brook T; Wyman, Stacia; Yang, Stephanie; Van Eyk, Jennifer E; Lloyd, Thomas E; Finkbeiner, Steven; Fraenkel, Ernest; Rothstein, Jeffrey D; Sareen, Dhruv; Svendsen, Clive N; Thompson, Leslie M.
Afiliação
  • Li J; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Lim RG; UCI MIND, University of California, Irvine, CA 92697, USA.
  • Kaye JA; Center for Systems and Therapeutics and the Taube/Koret Center for Neurodegenerative Disease, Gladstone Institutes, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Dardov V; The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
  • Coyne AN; Advanced Clinical Biosystems Research Institute, The Barbra Streisand Heart Center, The Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Wu J; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MA 212056, USA.
  • Milani P; Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MA 212056, USA.
  • Cheng A; Department of Biological Chemistry, University of California, Irvine, CA 92697, USA.
  • Thompson TG; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Ornelas L; Cellular and Molecular Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MA 212056, USA.
  • Frank A; UCI MIND, University of California, Irvine, CA 92697, USA.
  • Adam M; The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
  • Banuelos MG; The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
  • Casale M; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Cox V; The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
  • Escalante-Chong R; UCI MIND, University of California, Irvine, CA 92697, USA.
  • Daigle JG; Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA.
  • Gomez E; Cellular and Molecular Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MA 212056, USA.
  • Hayes L; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Holewenski R; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MA 212056, USA.
  • Lei S; Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MA 212056, USA.
  • Lenail A; The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
  • Lima L; Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MA 212056, USA.
  • Mandefro B; Advanced Clinical Biosystems Research Institute, The Barbra Streisand Heart Center, The Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Matlock A; The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
  • Panther L; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Patel-Murray NL; Center for Systems and Therapeutics and the Taube/Koret Center for Neurodegenerative Disease, Gladstone Institutes, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Pham J; The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
  • Ramamoorthy D; Advanced Clinical Biosystems Research Institute, The Barbra Streisand Heart Center, The Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Sachs K; The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
  • Shelley B; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Stocksdale J; Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MA 212056, USA.
  • Trost H; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Wilhelm M; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Venkatraman V; The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
  • Wassie BT; UCI MIND, University of California, Irvine, CA 92697, USA.
  • Wyman S; Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA.
  • Yang S; The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
  • Van Eyk JE; Advanced Clinical Biosystems Research Institute, The Barbra Streisand Heart Center, The Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Lloyd TE; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Finkbeiner S; Sue and Bill Gross Stem Cell Center, University of California, Irvine, CA 92697, USA.
  • Fraenkel E; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MA 212056, USA.
  • Sareen D; Advanced Clinical Biosystems Research Institute, The Barbra Streisand Heart Center, The Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Svendsen CN; Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MA 212056, USA.
  • Thompson LM; Center for Systems and Therapeutics and the Taube/Koret Center for Neurodegenerative Disease, Gladstone Institutes, University of California, San Francisco, San Francisco, CA 94158, USA.
iScience ; 24(11): 103221, 2021 Nov 19.
Article em En | MEDLINE | ID: mdl-34746695
ABSTRACT
Neurodegenerative diseases are challenging for systems biology because of the lack of reliable animal models or patient samples at early disease stages. Induced pluripotent stem cells (iPSCs) could address these challenges. We investigated DNA, RNA, epigenetics, and proteins in iPSC-derived motor neurons from patients with ALS carrying hexanucleotide expansions in C9ORF72. Using integrative computational methods combining all omics datasets, we identified novel and known dysregulated pathways. We used a C9ORF72 Drosophila model to distinguish pathways contributing to disease phenotypes from compensatory ones and confirmed alterations in some pathways in postmortem spinal cord tissue of patients with ALS. A different differentiation protocol was used to derive a separate set of C9ORF72 and control motor neurons. Many individual -omics differed by protocol, but some core dysregulated pathways were consistent. This strategy of analyzing patient-specific neurons provides disease-related outcomes with small numbers of heterogeneous lines and reduces variation from single-omics to elucidate network-based signatures.
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2021 Tipo de documento: Article
Texto completo
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PubMed Links
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2021 Tipo de documento: Article