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

• Published in: iScience 2021-11, Vol.24 (11), p.103221, Article 103221
• Main Authors: Phatnani, Hemali, Kwan, Justin, Sareen, Dhruv, Broach, James R., Simmons, Zachary, Arcila-Londono, Ximena, Lee, Edward B., Van Deerlin, Vivianna M., Shneider, Neil A., Fraenkel, Ernest, Ostrow, Lyle W., Baas, Frank, Zaitlen, Noah, Malaspina, Andrea, Fratta, Pietro, Cox, Gregory A., Thompson, Leslie M., Finkbeiner, Steve, Dardiotis, Efthimios, Chandran, Siddharthan, Pal, Suvankar, Hornstein, Eran, MacGowan, Daniel J., Heiman-Patterson, Terry, Hammell, Molly G., Patsopoulos, Nikolaos.A., Butovsky, Oleg, Dubnau, Joshua, Nath, Avindra, Bowser, Robert, Harms, Matt, Poss, Mary, Phillips-Cremins, Jennifer, Crary, John, Atassi, Nazem, Lange, Dale J., Adams, Darius J., Stefanis, Leonidas, Gotkine, Marc, Baloh, Robert H., Babu, Suma, Raj, Towfique, Paganoni, Sabrina, Shalem, Ophir, Smith, Colin, Zhang, Bin, Harris, Brent, Broce, Iris, Drory, Vivian, Ravits, John, McMillan, Corey, Menon, Vilas, Wu, Lani, Altschuler, Steven, 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, Rothstein, Jeffrey D., Svendsen, Clive N.
• Format: Article
• Language: English
• Subjects: Biological sciences; Neuroscience; Omics; Systems biology; Systems neuroscience
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2021.103221

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. [Display omitted] •Multi-omic analysis of differentiated C9ORF72 iPSC-derived motor neurons•Network-based integrative computational analysis•Pathogenic versus compensatory pathways elucidated using C9ORF72 Drosophila model•Pathways confirmed with alternative differentiation protocol and postmortem data Biological sciences; Neuroscience; Systems neuroscience; Systems biology; Omics