Cytochalasin D enhances the accumulation of a protease-resistant form of prion protein in ScN2a cells: involvement of PI3 kinase/Akt signalling pathway

Authors

  • Takato Takenouchi,

    Corresponding author
    1. Animal Immune and Cell Biology Research Unit, Division of Animal Sciences, National Institute of Agrobiological Sciences, 1-2 Ohwashi, Tsukuba, Ibaraki 305-8634, Japan
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    • These authors contributed equally to this work

  • Yoshifumi Iwamaru,

    1. Prion Disease Research Center, National Institute of Animal Health, 3-1-5 Kannondai, Tsukuba, Ibaraki 305-8602, Japan
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    • These authors contributed equally to this work

  • Morikazu Imamura,

    1. Prion Disease Research Center, National Institute of Animal Health, 3-1-5 Kannondai, Tsukuba, Ibaraki 305-8602, Japan
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  • Shigetomo Fukuhara,

    1. Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 5658565, Japan
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  • Shuei Sugama,

    1. Department of Physiology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan
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  • Mitsuru Sato,

    1. Animal Immune and Cell Biology Research Unit, Division of Animal Sciences, National Institute of Agrobiological Sciences, 1-2 Ohwashi, Tsukuba, Ibaraki 305-8634, Japan
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  • Naoki Mochizuki,

    1. Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 5658565, Japan
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  • Makoto Hashimoto,

    1. Division of Sensory and Motor Systems, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-0057, Japan
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  • Takashi Yokoyama,

    1. Prion Disease Research Center, National Institute of Animal Health, 3-1-5 Kannondai, Tsukuba, Ibaraki 305-8602, Japan
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  • Shirou Mohri,

    1. Prion Disease Research Center, National Institute of Animal Health, 3-1-5 Kannondai, Tsukuba, Ibaraki 305-8602, Japan
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  • Hiroshi Kitani

    Corresponding author
    1. Animal Immune and Cell Biology Research Unit, Division of Animal Sciences, National Institute of Agrobiological Sciences, 1-2 Ohwashi, Tsukuba, Ibaraki 305-8634, Japan
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(email ttakenou@affrc.go.jp or kitani@affrc.go.jp)

Abstract

The conversion of a host-encoded PrPsen (protease-sensitive cellular prion protein) into a PrPres (protease-resistant pathogenic form) is a key process in the pathogenesis of prion diseases, but the intracellular mechanisms underlying PrPres amplification in prion-infected cells remain elusive. To assess the role of cytoskeletal proteins in the regulation of PrPres amplification, the effects of cytoskeletal disruptors on PrPres accumulation in ScN2a cells that were persistently infected with the scrapie Chandler strain have been examined. Actin microfilament disruption with cytochalasin D enhanced PrPres accumulation in ScN2a cells. In contrast, the microtubule-disrupting agents, colchicine, nocodazole and paclitaxel, had no effect on PrPres accumulation. In addition, a PI3K (phosphoinositide 3-kinase) inhibitor, wortmannin and an Akt kinase inhibitor prevented the cytochalasin D-induced enhancement of PrPres accumulation. Cytochalasin D-induced extension of neurite-like processes might correlate with enhanced accumulation of PrPres. The results suggest that the actin cytoskeleton and PI3K/Akt pathway are involved in the regulation of PrPres accumulation in prion-infected cells.

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