Extracellular mutant SOD1 induces microglial-mediated motoneuron injury

Weihua Zhao, David R. Beers, Jenny S. Henkel, Wei Zhang, Makoto Urushitani, Jean Pierre Julien, Stanley H. Appel

Research output: Contribution to journalArticlepeer-review

229 Scopus citations


Through undefined mechanisms, dominant mutations in (Cu/Zn) superoxide dismutase-1 (mSOD1) cause the non-cellautonomous death of motoneurons in inherited amyotrophic lateral sclerosis (ALS). Microgliosis at sites of motoneuron injury is a neuropathological hallmark of ALS. Extracellular mutant SOD1 (mSOD1) causes motoneuron injury and triggers microgliosis in spinal cord cultures, but it is unclear whether the injury results from extracellular mSOD1 directly interacting with motoneurons or is mediated through mSOD1-activated microglia. To dissociate these potential mSOD1-mediated neurotoxic mechanisms, the effects of extracellular human mSOD1G93A or mSOD1G85R were assayed using primary cultures of motoneurons and microglia. The data demonstrate that exogenous mSOD1G93A did not cause detectable direct killing of motoneurons. In contrast, mSOD1G93A or mSOD1 G85R did induce the morphological and functional activation of microglia, increasing their release of pro-inflammatory cytokines and free radicals. Furthermore, only when microglia was co-cultured with motoneurons did extracellular mSOD1G93A injure motoneurons. The microglial activation mediated by mSOD1G93A was attenuated using toll-like receptors (TLR) 2, TLR4 and CD14 blocking antibodies, or when microglia lacked CD14 expression. These data suggest that extracellular mSOD1G93A is not directly toxic to motoneurons but requires microglial activation for toxicity, utilizing CD14 and TLR pathways. This link between mSOD1 and innate immunity may offer novel therapeutic targets in ALS.

Original languageEnglish (US)
Pages (from-to)231-243
Number of pages13
Issue number2
StatePublished - 2010


  • CD14
  • Microglia
  • Motoneurons
  • Mutant SOD1
  • Toll-like receptors

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Neurology


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