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

Stem Cell Reports. 2021 Dec 14;16(12):3020-3035. doi: 10.1016/j.stemcr.2021.10.010. Epub 2021 Nov 11.


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.

Keywords: ALS; SOD1; TGFβ; developmental pathways; iPSC; networks; single-cell RNA-seq; spinal MN.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / pathology*
  • Gene Expression Profiling*
  • Gene Expression Regulation
  • Gene Regulatory Networks
  • Humans
  • Induced Pluripotent Stem Cells / pathology*
  • Interneurons / metabolism
  • Motor Neurons / metabolism
  • Motor Neurons / pathology*
  • Nerve Degeneration / genetics*
  • Nerve Degeneration / pathology
  • Signal Transduction
  • Single-Cell Analysis*
  • Superoxide Dismutase-1 / metabolism*
  • Transforming Growth Factor beta / metabolism


  • Transforming Growth Factor beta
  • Superoxide Dismutase-1