1. An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients
- Author
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Consortium, The NeuroLINCS, 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, Berry, James D, Malaspina, Andrea, Fratta, Pietro, Cox, Gregory A, Thompson, Leslie M, Finkbeiner, Steve, Dardiotis, Efthimios, Miller, Timothy M, 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, Consortium, NYGC ALS, Van Eyk, Jennifer E, Lloyd, Thomas E, and Finkbeiner, Steven
- Subjects
Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Neurodegenerative ,Clinical Research ,ALS ,Stem Cell Research ,Rare Diseases ,Acquired Cognitive Impairment ,Stem Cell Research - Induced Pluripotent Stem Cell ,Brain Disorders ,Neurosciences ,Dementia ,Stem Cell Research - Induced Pluripotent Stem Cell - Human ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Good Health and Well Being ,NeuroLINCS Consortium ,NYGC ALS Consortium ,Biological sciences ,Neuroscience ,Omics ,Systems biology ,Systems neuroscience - 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.
- Published
- 2021