Translational profiling identifies a cascade of damage initiated in motor neurons and spreading to glia in mutant sod1-mediated ALS

Shuying Sun, Ying Sun, Shuo Chien Ling, Laura Ferraiuolo, Melissa McAlonis-Downes, Yiyang Zou, Kevin Drenner, Yin Wang, Dara Ditsworth, Seiya Tokunaga, Alex Kopelevich, Brian K. Kaspar, Clotilde Lagier-Tourenne, Don W. Cleveland

Research output: Contribution to journalArticlepeer-review

Abstract

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 PRKRlike 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.

Original languageEnglish (US)
Pages (from-to)E6993-E7002
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number50
DOIs
StatePublished - Dec 15 2015

Keywords

  • ALS
  • Bactrap
  • Cell type selective toxicity
  • RNA profiling
  • SOD1

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Translational profiling identifies a cascade of damage initiated in motor neurons and spreading to glia in mutant sod1-mediated ALS'. Together they form a unique fingerprint.

Cite this