Extracellular mutant SOD1 induces microglial-mediated motoneuron injury.

Publication Type:

Journal Article


Glia, Volume 58, Issue 2, p.231-43 (2010)


Animals, Antigens, CD14, Cell Death, Cells, Cultured, Coculture Techniques, Extracellular Space, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Microglia, Motor Neurons, Mutation, Missense, Recombinant Proteins, Signal Transduction, Spinal Cord, Superoxide Dismutase, Toll-Like Receptor 2, Toll-Like Receptor 4


<p>Through undefined mechanisms, dominant mutations in (Cu/Zn) superoxide dismutase-1 (mSOD1) cause the non-cell-autonomous 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 mSOD1(G93A) or mSOD1(G85R) were assayed using primary cultures of motoneurons and microglia. The data demonstrate that exogenous mSOD1(G93A) did not cause detectable direct killing of motoneurons. In contrast, mSOD1(G93A) 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 mSOD1(G93A) injure motoneurons. The microglial activation mediated by mSOD1(G93A) was attenuated using toll-like receptors (TLR) 2, TLR4 and CD14 blocking antibodies, or when microglia lacked CD14 expression. These data suggest that extracellular mSOD1(G93A) 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.</p>

Funding / Support / Partners

logo FRQ-S logo ctrn logo fci logo cihr irsc logo nserc logo MESISentinelle nord