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

Phatnani, H, Kwan, J, Sareen, D, Broach, JR, Simmons, Z, Arcila-Londono, X, Lee, EB, Van Deerlin, VM, Shneider, NA, Fraenkel, E, Ostrow, LW, Baas, F, Zaitlen, N, Berry, JD, Malaspina, A, Fratta, P, Cox, GA, Thompson, LM, Finkbeiner, S, Dardiotis, E, Miller, TM, Chandran, S, Pal, S, Hornstein, E, MacGowan, DJ, Heiman-Patterson, T, Hammell, MG, Patsopoulos, NA, Butovsky, O, Dubnau, J, Nath, A, Bowser, R, Harms, M, Poss, M, Phillips-Cremins, J, Crary, J, Atassi, N, Lange, DJ, Adams, DJ, Stefanis, L, Gotkine, M, Baloh, RH, Babu, S, Raj, T, Paganoni, S, Shalem, O, Smith, C, Zhang, B, Harris, B, Broce, I, Drory, V, Ravits, J, McMillan, C, Menon, V, Wu, L, Altschuler, S, Li, J, Lim, RG, Kaye, JA, Dardov, V, Coyne, AN, Wu, J, Milani, P, Cheng, A, Thompson, TG, Ornelas, L, Frank, A, Adam, M, Banuelos, MG, Casale, M, Cox, V, Escalante-Chong, R, Daigle, JG, Gomez, E, Hayes, L, Holewenski, R, Lei, S, Lenail, A, Lima, L, Mandefro, B, Matlock, A, Panther, L, Patel-Murray, NL, Pham, J, Ramamoorthy, D, Sachs, K, Shelley, B, Stocksdale, J, Trost, H, Wilhelm, M, Venkatraman, V, Wassie, BT, Wyman, S, Yang, S, Van Eyk, JE, Lloyd, TE, Finkbeiner, S, Rothstein, JD, Svendsen, CN (November 2021) An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients. iScience, 24 (11). p. 103221. ISSN 2589-0042

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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.

Item Type:	Paper
Subjects:	diseases & disorders > nervous system diseases and disorders > amyotrophic lateral sclerosis organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neurons > motor neurons organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neurons > motor neurons organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neurons > motor neurons organs, tissues, organelles, cell types and functions > cell types and functions > cell types > stem cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > stem cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > stem cells
CSHL Authors:	Hammell, Molly
Communities:	CSHL labs > Hammell M. lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	19 November 2021
Date Deposited:	03 Feb 2022 19:15
Last Modified:	03 Feb 2022 19:15
PMCID:	PMC8554488
URI:	https://repository.cshl.edu/id/eprint/40511

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