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

The NeuroLINCS Consortium, NYGC ALS Consortium

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number103221
JournaliScience
Volume24
Issue number11
DOIs
StatePublished - 19 Nov 2021

Funding

FundersFunder number
National Institutes of HealthNS085207, NS094239, NS089076, U54 NS091046
National Institutes of Health
ALS Association
Fidelity Biosciences
University of California, Irvine
Tow FoundationCA-62203
Tow Foundation

    Keywords

    • Biological sciences
    • Neuroscience
    • Omics
    • Systems biology
    • Systems neuroscience

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