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Major histocompatibility complex class I molecules protect motor neurons from astrocyte-induced toxicity in amyotrophic lateral sclerosis

Abstract

Astrocytes isolated from individuals with amyotrophic lateral sclerosis (ALS) are toxic to motor neurons (MNs) and play a non–cell autonomous role in disease pathogenesis. The mechanisms underlying the susceptibility of MNs to cell death remain unclear. Here we report that astrocytes derived from either mice bearing mutations in genes associated with ALS or human subjects with ALS reduce the expression of major histocompatibility complex class I (MHCI) molecules on MNs; reduced MHCI expression makes these MNs susceptible to astrocyte-induced cell death. Increasing MHCI expression on MNs increases survival and motor performance in a mouse model of ALS and protects MNs against astrocyte toxicity. Overexpression of a single MHCI molecule, HLA-F, protects human MNs from ALS astrocyte–mediated toxicity, whereas knockdown of its receptor, the killer cell immunoglobulin-like receptor KIR3DL2, on human astrocytes results in enhanced MN death. Thus, our data indicate that, in ALS, loss of MHCI expression on MNs renders them more vulnerable to astrocyte-mediated toxicity.

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Figure 1: MHCI expression is reduced on spinal MNs in end-stage ALS.
Figure 2: ALS astrocytes induce downregulation of MHCI expression in MNs.
Figure 3: H2k expression protects MNs from ALS astrocyte–induced toxicity and delays disease progression in SOD1G93A mice.
Figure 4: ALS astrocytes express MHCI inhibitory receptors.
Figure 5: HLA-F expression protects human MNs from ALS astrocyte–induced toxicity.

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Acknowledgements

We thank C. Shatz (Stanford University) for critical discussions; S. Eckardt for expert editorial assistance; the National Disease Research Institute (NDRI), A. Burghes (Ohio State University), J.R. Mendell (Nationwide Children's Hospital), J. Glass and M. Gearing (Emory University; supported by US National Institutes of Health (NIH)-NINDS grant no. P30NS055077) for providing human spinal cord specimens; F. Gage (Salk Institute) for providing human post-mortem neural progenitor cells (NPCs) that were used to generate non-ALS astrocytes; M. Hester for guidance with iPSC generation; T. Jessell (Columbia University) for HBG3 cells; and K. Campbell for technical assistance. This work was supported by NIH grants R01-NS644912 (B.K.K.) and RC2-NS69476 (B.K.K.), funding from the Robert Packard Center for ALS Research (B.K.K.), the Project A.L.S. (B.K.K.) and the Helping Link Foundation (B.K.K.). The authors that were a part of this work also received research fellowships from the Swiss National Science Foundation (K.M.), the Marie Curie Foundation (L.F.), the NINDS Training in Neuromuscular Disease (A.E.F.), the Ohio State University Presidential Fellowship (S.W.S.) and the Ohio State University and Nationwide Children's Hospital Muscle Group Fellowship (S.W.S.).

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All authors contributed to the design of the experiments. Isolation of mouse astrocytes, microglia and NPCs was performed by S.W.S., C.J.M., L.B., A.E.F. and S.L.; human astrocyte cultures were done by S.W.S., C.J.M., K.M. and L.F.; neuronal cell differentiation and coculture experiments were performed by S.W.S., C.J.M., K.M., A.E.F. and S.L.; in situ hybridization of H2d transcripts was performed by M.J.M.; RT-PCR and immunocytochemistry analyses were done by S.W.S., C.J.M., L.B. and A.K.B.; lentivirus production was done by S.W.S., C.J.M., L.B., K.M., A.E.F., L.F. and S.L.; and data was analyzed by S.W.S., C.J.M., L.B., K.M., A.E.F., L.F., S.L., A.K.B., K.D.F., M.J.M., C.M.W. and B.K.K. The manuscript and figures were prepared by S.W.S., C.J.M. and B.K.K., with input from all coauthors.

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Correspondence to Brian K Kaspar.

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Song, S., Miranda, C., Braun, L. et al. Major histocompatibility complex class I molecules protect motor neurons from astrocyte-induced toxicity in amyotrophic lateral sclerosis. Nat Med 22, 397–403 (2016). https://doi.org/10.1038/nm.4052

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