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Published online
doi:10.1083/jcb.200705046
The Journal of Cell Biology, Vol. 179, No. 6, 1219-1230
The Rockefeller University Press, 0021-9525 $30.00
© Kang et al.
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Article

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



Jihong Kang and Serge Rivest

Laboratory of Molecular Endocrinology, Centre hospitalier de l'Université Laval Research Center and Department of Anatomy and Physiology, Laval University, Québec G1V 4G2, Canada

Correspondence to S. Rivest: serge.rivest{at}crchul.ulaval.ca

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 SOD1G37R and SOD1G93A mice by transplantation of bone marrow (BM) cells from MyD88-deficient or green fluorescent protein (GFP)–expressing mice. SOD1G37R 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.

Abbreviations used in this paper: ALS, amyotrophic lateral sclerosis; APP, amyloid precursor protein; BM, bone marrow; BMDM, BM-derived microglia; CNS, central nervous system; FJB, fluoro-Jade B; IL, interleukin; MCP-1, monocyte chemoattractant protein 1; MyD88, myeloid differentiation factor 88; PLP1, proteolipid protein 1; SOD, superoxide dismutase; TLR2, toll-like receptor 2; WT, wild type.


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