Motor neurons from ALS patients with mutations in C9ORF72 and SOD1 exhibit distinct transcriptional landscapes

Hum Mol Genet. 2019 Aug 15;28(16):2799-2810. doi: 10.1093/hmg/ddz104.


Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease that culminates in paralysis and death. Here, we present our analyses of publicly available multiOMIC data sets generated using motor neurons from ALS patients and control cohorts. Functional annotation of differentially expressed genes in induced pluripotent stem cell (iPSC)-derived motor neurons generated from patients with mutations in C9ORF72 (C9-ALS) suggests elevated expression of genes that pertain to extracellular matrix (ECM) and cell adhesion, inflammation and TGFβ targets. On the other end of the continuum, we detected diminished expression of genes repressed by quiescence-promoting E2F4/DREAM complex. Proteins whose abundance was significantly altered in C9-ALS neurons faithfully recapitulated the transcriptional aberrations. Importantly, patterns of gene expression in spinal motor neurons dissected from C9-ALS or sporadic ALS patients were highly concordant with each other and with the C9-ALS iPSC neurons. In contrast, motor neurons from patients with mutations in SOD1 exhibited dramatically different signatures. Elevated expression of gene sets such as ECM and cell adhesion genes occurs in C9 and sporadic ALS but not SOD1-ALS. These analyses indicate that despite the similarities in outward manifestations, transcriptional and proteomic signatures in ALS motor neurons can vary significantly depending on the identity of the causal mutations.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / physiopathology
  • C9orf72 Protein / genetics*
  • Computational Biology / methods
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Gene Regulatory Networks
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism
  • Models, Biological
  • Motor Neurons / cytology
  • Motor Neurons / metabolism*
  • Mutation*
  • Proteomics / methods
  • Superoxide Dismutase-1 / genetics*
  • Transcription, Genetic*


  • C9orf72 Protein
  • C9orf72 protein, human
  • SOD1 protein, human
  • Superoxide Dismutase-1