Translational profiling identifies a cascade of damage initiated in motor neurons and spreading to glia in mutant SOD1-mediated ALS

Proc Natl Acad Sci U S A. 2015 Dec 15;112(50):E6993-7002. doi: 10.1073/pnas.1520639112. Epub 2015 Nov 30.


Ubiquitous expression of amyotrophic lateral sclerosis (ALS)-causing mutations in superoxide dismutase 1 (SOD1) provokes noncell autonomous paralytic disease. By combining ribosome affinity purification and high-throughput sequencing, a cascade of mutant SOD1-dependent, cell type-specific changes are now identified. Initial mutant-dependent damage is restricted to motor neurons and includes synapse and metabolic abnormalities, endoplasmic reticulum (ER) stress, and selective activation of the PRKR-like ER kinase (PERK) arm of the unfolded protein response. PERK activation correlates with what we identify as a naturally low level of ER chaperones in motor neurons. Early changes in astrocytes occur in genes that are involved in inflammation and metabolism and are targets of the peroxisome proliferator-activated receptor and liver X receptor transcription factors. Dysregulation of myelination and lipid signaling pathways and activation of ETS transcription factors occur in oligodendrocytes only after disease initiation. Thus, pathogenesis involves a temporal cascade of cell type-selective damage initiating in motor neurons, with subsequent damage within glia driving disease propagation.

Keywords: ALS; RNA profiling; SOD1; bacTRAP; cell type selective toxicity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Gene Expression Profiling*
  • Humans
  • Mice
  • Motor Neurons / metabolism*
  • Motor Neurons / pathology
  • Mutation*
  • Neuroglia / metabolism*
  • Neuroglia / pathology
  • Protein Biosynthesis*
  • Superoxide Dismutase / genetics*
  • Superoxide Dismutase-1


  • SOD1 protein, human
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1

Associated data

  • GEO/GSE74724