MyD88-deficient bone marrow cells accelerate onset and reduce survival in a mouse model of amyotrophic lateral sclerosis

Increasing evidence suggests that neurotoxicity of secreted superoxide dismutase 1 (SOD1) mutants is associated with amyotrophic lateral sclerosis (ALS). We show here that mutant SOD1 protein activates microglia via a myeloid differentiation factor 88 (MyD88)–dependent pathway. This inflammatory response is also associated with a marked recruitment of bone marrow–derived microglia (BMDM) in the central nervous system. We then generated chimeric SOD1^G37R and SOD1^G93A mice by transplantation of bone marrow (BM) cells from MyD88-deficient or green fluorescent protein (GFP)–expressing mice. SOD1^G37R mice receiving MyD88^−/− BM cells exhibit a significantly earlier disease onset and shorter lifespan compared with mice transplanted with control GFP cells. This compelling beneficial effect of MyD88-competent BMDM is a previously unrecognized natural innate immune mechanism of neuroprotection in a mouse model of late-onset motor neuron disease.