文章基本信息

标题：An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients
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作者：Jonathan Li ; Ryan G. Lim ; Julia A. Kaye 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2021
卷号：24
期号：11
页码：1-33
DOI：10.1016/j.isci.2021.103221
语种：English
出版社：Elsevier
摘要：SummaryNeurodegenerative 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 inC9ORF72. Using integrative computational methods combining all omics datasets, we identified novel and known dysregulated pathways. We used aC9ORF72Drosophila 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 ofC9ORF72and 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.Graphical abstractDisplay OmittedHighlights•Multi-omic analysis of differentiated C9ORF72 iPSC-derived motor neurons•Network-based integrative computational analysis•Pathogenic versus compensatory pathways elucidated using C9ORF72Drosophilamodel•Pathways confirmed with alternative differentiation protocol and postmortem dataBiological sciences; Neuroscience; Systems neuroscience; Systems biology; Omics