Abstract
Sandhoff disease (SD) is a lysosomal β-hexosaminidase (Hex) deficiency involving excessive accumulation of undegraded substrates, including GM2 ganglioside, and progressive neurodegeneration. Macrophage inflammatory protein-1α (MIP-1α) is a crucial factor for microglia-mediated neuroinflammation in the onset or progression of SD. However, the transmitter-mediated production of MIP-1α in SD is still poorly understood.
Extracellular nucleotides, including uridine diphosphate (UDP), leaked by either injured or damaged neuronal cells activate microglia to trigger chemotaxis, phagocytosis, macropinocytosis, and cytokine production.
In this study, we demonstrated that UDP enhanced the production of MIP-1α by microglia derived from SD mice (SD-Mg), but not that from wild-type mice (WT-Mg). The UDP-induced MIP-1α production was mediated by the activation of P2Y6 receptor, ERK, and JNK. We also found the amount of dimeric P2Y6 receptor protein to have increased in SD-Mg in comparison to WT-Mg. In addition, we demonstrated that the disruption of lipid rafts enhanced the effect of UDP on MIP-1α production and the disordered maintenance of the lipid rafts in SD-Mg. Thus, the accumulation of undegraded substrates might cause the enhanced effect of UDP in SD-Mg through the increased expression of the dimeric P2Y6 receptors and the disordered maintenance of the lipid rafts. These findings provide new insights into the pathogenic mechanism and therapeutic strategies for SD.
Competing interests: None declared
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Acknowledgments
Technical support for the experiments was provided by Dr. K. Nakayama from National Institute of Advanced Industrial Science and Technology.
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Communicated by: Johannes Häberle
Synopsis
UDP enhances MIP-1α production through the increased expression of the dimeric P2Y6 receptors and the disordered maintenance of the lipid rafts in microglia derived from Sandhoff disease model mice.
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Eri Kawashita, Daisuke Tsuji, Yosuke Kanno, Kaho Tsuchida, and Kohji Itoh declare that they have no conflict of interest.
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All institutional and national guidelines for the care and use of laboratory animals were followed.
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EK and KI planned the experiments. EK and DT conducted the experiments. EK, DT, and KT analyzed the data. EK, DT, YK, KT, and KI interpreted the data. EK wrote the paper.
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Kawashita, E., Tsuji, D., Kanno, Y., Tsuchida, K., Itoh, K. (2015). Enhancement by Uridine Diphosphate of Macrophage Inflammatory Protein-1 Alpha Production in Microglia Derived from Sandhoff Disease Model Mice. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 28. JIMD Reports, vol 28. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2015_496
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DOI: https://doi.org/10.1007/8904_2015_496
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