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Effects of prion protein devoid of the N-terminal residues 25-50 on prion pathogenesis in mice

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Abstract

The N-terminal polybasic region of the normal prion protein, PrPC, which encompasses residues 23-31, is important for prion pathogenesis by affecting conversion of PrPC into the pathogenic isoform, PrPSc. We previously reported transgenic mice expressing PrP with residues 25-50 deleted in the PrP-null background, designated as Tg(PrP∆preOR)/Prnp 0/0 mice. Here, we produced two new lines of Tg(PrP∆preOR)/Prnp 0/0 mice, each expressing the mutant protein, PrP∆preOR, 1.1 and 1.6 times more than PrPC in wild-type mice, and subsequently intracerebrally inoculated RML and 22L prions into them. The lower expresser showed slightly reduced susceptibility to RML prions but not to 22L prions. The higher expresser exhibited enhanced susceptibility to both prions. No prion transmission barrier was created in Tg(PrP∆preOR)/Prnp 0/0 mice against full-length PrPSc. PrPSc∆preOR accumulated in the brains of infected Tg(PrP∆preOR)/Prnp 0/0 mice less than PrPSc in control wild-type mice, although lower in RML-infected Tg(PrP∆preOR)/Prnp 0/0 mice than in 22L-infected mice. Prion infectivity in infected Tg(PrP∆preOR)/Prnp 0/0 mice was also lower than that in wild-type mice. These results indicate that deletion of residues 25-50 only slightly affects prion susceptibility, the conversion of PrPC into PrPSc, and prion infectivity in a strain-specific way. PrP∆preOR retains residues 23-24 and lacks residues 25-31 in the polybasic region. It is thus conceivable that residues 23-24 rather than 25-31 are important for the polybasic region to support prion pathogenesis. However, other investigators have reported that residues 27-31 not 23-24 are important to support prion pathogenesis. Taken together, the polybasic region might support prion pathogenesis through multiple sites including residues 23-24 and 27-31.

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Acknowledgements

We thank Dr. Stanley B. Prusiner for providing Zrch I Prnp 0/0 mice.

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Authors and Affiliations

  1. Division of Molecular Neurobiology, Institute for Enzyme Research (KOSOKEN), Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan

    Nandita Rani Das, Hideyuki Hara, Keiji Uchiyama, Junji Chida, Masashi Yano & Suehiro Sakaguchi

  2. Animal Research Center, School of Medicine, University of Occupational and Environmental Health, Yahatanishi, Kitakyushu, Japan

    Hironori Miyata

  3. Laboratory of Integrative Biological Science, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan

    Hitomi Watanabe & Gen Kondoh

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  1. Nandita Rani Das
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  2. Hironori Miyata
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  3. Hideyuki Hara
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  4. Keiji Uchiyama
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  5. Junji Chida
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  7. Hitomi Watanabe
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  8. Gen Kondoh
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  9. Suehiro Sakaguchi
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Correspondence to Suehiro Sakaguchi.

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Funding

This work was supported in part by Pilot Research Support Program in Tokushima University, the Naito Foundation, JSPS KAKENHI grant numbers, JP26460557, JP26293212, MEXT KAKENHI grant numbers, J15H01560, and the Practical Research Project for Rare/Intractable Diseases of the Japan Agency for Medical Research and Development (AMED). H. M was partly supported by a Cooperative Research Grant of the Institute for Enzyme Research, Tokushima University.

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The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants performed by any of the authors. All animal experiments in this study were performed according to the regulations and guidelines for animal ethics of The Guiding Principle for Animal Care and Experimentation of Tokushima University, the University of Occupational and Environmental Health, and Japanese Law for Animal Welfare and Care, with prior approval of The Ethics Committee of Animal Care and Experimentation of Tokushima University and the University of Occupational and Environmental Health (approval number T27-102, AE08-013).

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Das, N.R., Miyata, H., Hara, H. et al. Effects of prion protein devoid of the N-terminal residues 25-50 on prion pathogenesis in mice. Arch Virol 162, 1867–1876 (2017). https://doi.org/10.1007/s00705-017-3295-3

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