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.
Kang
Jihong
J
Laboratory of Molecular Endocrinology, Centre hospitalier de l'Université Laval Research Center and Department of Anatomy and Physiology, Laval University, Québec G1V 4G2, Canada.
Rivest
Serge
S
D017668:Age of Onset; D000690:Amyotrophic Lateral Sclerosis / Q000453:epidemiology / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000648:ultrastructure; D001854:Bone Marrow Cells / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D002678:Chimera / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D008136:Longevity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D009046:Motor Neurons / Q000473:pathology; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D015398:Signal Transduction; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1
C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1