4.6 Article

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

Journal

STEM CELL REPORTS
Volume 16, Issue 12, Pages 3020-3035

Publisher

CELL PRESS
DOI: 10.1016/j.stemcr.2021.10.010

Keywords

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Funding

  1. Wellcome Trust Institutional Strategic Sup-port Award [WT204909MA]
  2. Joint Council Office ASTAR, Singapore
  3. AMS Springboard Award [SBF003\1182]
  4. MRC [MR/T033029/1]
  5. University of Exeter, U.K
  6. UKRI EPSRC Inno-vation Fellowship
  7. BBSRC-funded South West Biosciences Doctoral Training Partnership [BB/J014400/1, BB/M009122/1]
  8. MRC [MR/T033029/1] Funding Source: UKRI

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Using single-cell transcriptomics, researchers identified activation of developmental pathways and core transcriptional factors in motor neurons of ALS patients, leading to gene dysregulation. The activation of TGFβ signaling may be a common mechanism shared by various types of ALS.
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 beta (TGF-beta) signaling pathway as a key driver of SOD1 iPSC-derived motor neuron degeneration. Importantly, our analysis indicates that activation of TGFP 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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