An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients

NeuroLINCS Consortium; Jonathan Li; Ryan G Lim; Julia A Kaye; Victoria Dardov; Alyssa N Coyne; Jie Wu; Pamela Milani; Andrew Cheng; Terri G Thompson; Loren Ornelas; Aaron Frank; Miriam Adam; Maria G Banuelos; Malcolm Casale; Veerle Cox; Renan Escalante-Chong; J Gavin Daigle; Emilda Gomez; Lindsey Hayes; Ronald Holewenski; Susan Lei; Alex Lenail; Leandro Lima; Berhan Mandefro; Andrea Matlock; Lindsay Panther; Natasha Leanna Patel-Murray; Jacqueline Pham; Divya Ramamoorthy; Karen Sachs; Brandon Shelley; Jennifer Stocksdale; Hannah Trost; Mark Wilhelm; Vidya Venkatraman; Brook T Wassie; Stacia Wyman; Stephanie Yang; NYGC ALS Consortium; Jennifer E Van Eyk; Thomas E Lloyd; Steven Finkbeiner; Ernest Fraenkel; Jeffrey D Rothstein; Dhruv Sareen; Clive N Svendsen; Leslie M Thompson

doi:10.1016/j.isci.2021.103221

An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients

iScience. 2021 Oct 12;24(11):103221. doi: 10.1016/j.isci.2021.103221. eCollection 2021 Nov 19.

Authors

NeuroLINCS Consortium; Jonathan Li¹, Ryan G Lim², Julia A Kaye³, Victoria Dardov^{4

5}, Alyssa N Coyne^{6

7}, Jie Wu⁸, Pamela Milani¹, Andrew Cheng⁹, Terri G Thompson², Loren Ornelas⁴, Aaron Frank⁴, Miriam Adam¹, Maria G Banuelos⁴, Malcolm Casale^{2

10}, Veerle Cox⁹, Renan Escalante-Chong¹, J Gavin Daigle^{6

7}, Emilda Gomez⁴, Lindsey Hayes⁷, Ronald Holewenski⁵, Susan Lei⁴, Alex Lenail¹, Leandro Lima³, Berhan Mandefro⁴, Andrea Matlock⁵, Lindsay Panther⁴, Natasha Leanna Patel-Murray¹, Jacqueline Pham⁷, Divya Ramamoorthy¹, Karen Sachs¹, Brandon Shelley⁴, Jennifer Stocksdale^{2

10}, Hannah Trost⁴, Mark Wilhelm⁶, Vidya Venkatraman⁵, Brook T Wassie¹, Stacia Wyman¹¹, Stephanie Yang⁶; NYGC ALS Consortium; Jennifer E Van Eyk⁵, Thomas E Lloyd⁷, Steven Finkbeiner^{3

12}, Ernest Fraenkel¹, Jeffrey D Rothstein^{6

7

9}, Dhruv Sareen⁴, Clive N Svendsen⁴, Leslie M Thompson^{2

8

10

13

11}

Collaborators

Hemali Phatnani, Justin Kwan, Dhruv Sareen, James R Broach, Zachary Simmons, Ximena Arcila-Londono, Edward B Lee, Vivianna M Van Deerlin, Neil A Shneider, Ernest Fraenkel, Lyle W Ostrow, Frank Baas, Noah Zaitlen, James D Berry, Andrea Malaspina, Pietro Fratta, Gregory A Cox, Leslie M Thompson, Steve Finkbeiner, Efthimios Dardiotis, Timothy M Miller, Siddharthan Chandran, Suvankar Pal, Eran Hornstein, Daniel J MacGowan, Terry Heiman-Patterson, Molly G Hammell, Nikolaos A Patsopoulos, Oleg Butovsky, Joshua Dubnau, Avindra Nath, Robert Bowser, Matt Harms, Mary Poss, Jennifer Phillips-Cremins, John Crary, Nazem Atassi, Dale J Lange, Darius J Adams, Leonidas Stefanis, Marc Gotkine, Robert H Baloh, Suma Babu, Towfique Raj, Sabrina Paganoni, Ophir Shalem, Colin Smith, Bin Zhang, Brent Harris, Iris Broce, Vivian Drory, John Ravits, Corey McMillan, Vilas Menon, Lani Wu, Steven Altschuler

Affiliations

¹ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
² UCI MIND, University of California, Irvine, CA 92697, USA.
³ 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.
⁴ The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
⁵ Advanced Clinical Biosystems Research Institute, The Barbra Streisand Heart Center, The Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁶ Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MA 212056, USA.
⁷ Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MA 212056, USA.
⁸ Department of Biological Chemistry, University of California, Irvine, CA 92697, USA.
⁹ Cellular and Molecular Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MA 212056, USA.
¹⁰ Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA.
¹¹ Sue and Bill Gross Stem Cell Center, University of California, Irvine, CA 92697, USA.
¹² Departments of Neurology and Physiology, University of California, San Francisco, San Francisco, CA 94158, USA.
¹³ Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697, USA.

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.

Keywords: Biological sciences; Neuroscience; Omics; Systems biology; Systems neuroscience.

Abstract

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