Single-cell transcriptomics identifies master regulators of neurodegeneration in SOD1 ALS iPSC-derived motor neurons

Seema C. Namboori; Patricia Thomas; Ryan Ames; Sophie Hawkins; Lawrence O. Garrett; Craig R. G. Willis; Alessandro Rosa; Lawrence W. Stanton; Akshay Bhinge

doi:10.1016/j.stemcr.2021.10.010

Single-cell transcriptomics identifies master regulators of neurodegeneration in SOD1 ALS iPSC-derived motor neurons

Seema C. Namboori, Patricia Thomas, Ryan Ames, Sophie Hawkins, Lawrence O. Garrett, Craig R. G. Willis, Alessandro Rosa, Lawrence W. Stanton, Akshay Bhinge

Metabolism and Systems Research

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Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition characterized by the loss of motor neurons. We utilized single-cell transcriptomics to uncover dysfunctional pathways in degenerating motor neurons differentiated from SOD1 E100G ALS patient-derived induced pluripotent stem cells (iPSCs) and respective isogenic controls. Differential gene expression and network analysis identified activation of developmental pathways and core transcriptional factors driving the ALS motor neuron gene dysregulation. Specifically, we identified activation of SMAD2, a downstream mediator of the transforming growth factor β (TGF-β) signaling pathway as a key driver of SOD1 iPSC-derived motor neuron degeneration. Importantly, our analysis indicates that activation of TGFβ signaling may be a common mechanism shared between SOD1, FUS, C9ORF72, VCP, and sporadic ALS motor neurons. Our results demonstrate the utility of single-cell transcriptomics in mapping disease-relevant gene regulatory networks driving neurodegeneration in ALS motor neurons. We find that ALS-associated mutant SOD1 targets transcriptional networks that perturb motor neuron homeostasis.

Original language	English
Pages (from-to)	3020-3035
Journal	Stem Cell Reports
Volume	16
Issue number	12
Early online date	11 Nov 2021
DOIs	https://doi.org/10.1016/j.stemcr.2021.10.010
Publication status	Published - 14 Dec 2021

Bibliographical note

Acknowledgments
We thank the sequencing center at the Genome Institute of Singapore for help with Illumina sequencing. This work was generously supported by the Wellcome Trust Institutional Strategic Support Award (WT204909MA) and the Joint Council Office ASTAR, Singapore. A.B. is funded by an AMS Springboard Award (SBF003\1182), an MRC grant (MR/T033029/1), and University of Exeter, U.K. start-up funds. R.A. is supported by a UKRI EPSRC Innovation Fellowship. C.R.G.W. is supported by the BBSRC-funded South West Biosciences Doctoral Training Partnership (BB/J014400/1; BB/M009122/1).

Keywords

ALS
SOD1
TGFβ
developmental pathways
iPSC
networks
single-cell RNA-seq
spinal MN

ASJC Scopus subject areas

Biochemistry
Genetics
Developmental Biology
Cell Biology

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Cite this

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title = "Single-cell transcriptomics identifies master regulators of neurodegeneration in SOD1 ALS iPSC-derived motor neurons",

abstract = "Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition characterized by the loss of motor neurons. We utilized single-cell transcriptomics to uncover dysfunctional pathways in degenerating motor neurons differentiated from SOD1 E100G ALS patient-derived induced pluripotent stem cells (iPSCs) and respective isogenic controls. Differential gene expression and network analysis identified activation of developmental pathways and core transcriptional factors driving the ALS motor neuron gene dysregulation. Specifically, we identified activation of SMAD2, a downstream mediator of the transforming growth factor β (TGF-β) signaling pathway as a key driver of SOD1 iPSC-derived motor neuron degeneration. Importantly, our analysis indicates that activation of TGFβ signaling may be a common mechanism shared between SOD1, FUS, C9ORF72, VCP, and sporadic ALS motor neurons. Our results demonstrate the utility of single-cell transcriptomics in mapping disease-relevant gene regulatory networks driving neurodegeneration in ALS motor neurons. We find that ALS-associated mutant SOD1 targets transcriptional networks that perturb motor neuron homeostasis.",

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note = "Acknowledgments We thank the sequencing center at the Genome Institute of Singapore for help with Illumina sequencing. This work was generously supported by the Wellcome Trust Institutional Strategic Support Award (WT204909MA) and the Joint Council Office ASTAR, Singapore. A.B. is funded by an AMS Springboard Award (SBF003\1182), an MRC grant (MR/T033029/1), and University of Exeter, U.K. start-up funds. R.A. is supported by a UKRI EPSRC Innovation Fellowship. C.R.G.W. is supported by the BBSRC-funded South West Biosciences Doctoral Training Partnership (BB/J014400/1; BB/M009122/1).",

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AU - Namboori, Seema C.

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AU - Garrett, Lawrence O.

AU - Willis, Craig R. G.

AU - Rosa, Alessandro

AU - Stanton, Lawrence W.

AU - Bhinge, Akshay

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N2 - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition characterized by the loss of motor neurons. We utilized single-cell transcriptomics to uncover dysfunctional pathways in degenerating motor neurons differentiated from SOD1 E100G ALS patient-derived induced pluripotent stem cells (iPSCs) and respective isogenic controls. Differential gene expression and network analysis identified activation of developmental pathways and core transcriptional factors driving the ALS motor neuron gene dysregulation. Specifically, we identified activation of SMAD2, a downstream mediator of the transforming growth factor β (TGF-β) signaling pathway as a key driver of SOD1 iPSC-derived motor neuron degeneration. Importantly, our analysis indicates that activation of TGFβ signaling may be a common mechanism shared between SOD1, FUS, C9ORF72, VCP, and sporadic ALS motor neurons. Our results demonstrate the utility of single-cell transcriptomics in mapping disease-relevant gene regulatory networks driving neurodegeneration in ALS motor neurons. We find that ALS-associated mutant SOD1 targets transcriptional networks that perturb motor neuron homeostasis.

AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition characterized by the loss of motor neurons. We utilized single-cell transcriptomics to uncover dysfunctional pathways in degenerating motor neurons differentiated from SOD1 E100G ALS patient-derived induced pluripotent stem cells (iPSCs) and respective isogenic controls. Differential gene expression and network analysis identified activation of developmental pathways and core transcriptional factors driving the ALS motor neuron gene dysregulation. Specifically, we identified activation of SMAD2, a downstream mediator of the transforming growth factor β (TGF-β) signaling pathway as a key driver of SOD1 iPSC-derived motor neuron degeneration. Importantly, our analysis indicates that activation of TGFβ signaling may be a common mechanism shared between SOD1, FUS, C9ORF72, VCP, and sporadic ALS motor neurons. Our results demonstrate the utility of single-cell transcriptomics in mapping disease-relevant gene regulatory networks driving neurodegeneration in ALS motor neurons. We find that ALS-associated mutant SOD1 targets transcriptional networks that perturb motor neuron homeostasis.

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Single-cell transcriptomics identifies master regulators of neurodegeneration in SOD1 ALS iPSC-derived motor neurons

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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