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Impaired Motor Coordination in Mice Lacking Prion Protein

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Abstract

1. Prion protein (PrPC) is a host-encoded glycoprotein constitutively expressed on the neuronal cell surface. Accumulation of its protease-resistant isoform is closely related to pathologic changes and prion propagation in the brain tissue of a series of prion diseases. However, the physiological role of PrPC remains to be elucidated.

2. After long-term observation, we noted impaired motor coordination and loss of cerebellar Purkinje cells in the aged mice homozygous for a disrupted PrP gene, a finding which strongly suggests that PrPC plays a role in the long-term survival of Purkinje cells.

3. We also describe the resistance of the PrP null mice to the prion, indicating the requirement of PrPC for both the development of prion diseases and the prion propagation.

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REFERENCES

  • Basler, K., Oesch, B., Scott, M., Westaway, D., Walchli, M., Groth, D. F., McKinley, M. P., Prusiner, S. B., and Weissmann, C. (1986). Scrapie and cellular PrP isoforms are encoded by the same chromosomal gene. Cell 46:417–428.

    Google Scholar 

  • Bolton, D. C., McKinley, M. P., and Prusiner, S. B. (1982). Identification of a protein that purifies with the scrapie prion. Science 218:1309–1311.

    Google Scholar 

  • Brown, P., Gibbs, C. J., Rodgers-Johnson, P., Asher, D. M., Sulima, M. P., Bacote, A., Goldfarb, L. G., and Gajdusek, D. C. (1994). Human spongiform encephalopathy: The National Institutes of Health series of 300 cases of experimentally transmitted disease. Ann. Neurol. 35:513–529.

    Google Scholar 

  • Bruce, M. E., and Dickinson, A. G. (1987). Biological evidence that scrapie agent has an independent genome. J. Gen. Virol. 68:79–89.

    Google Scholar 

  • Büeler, H., Fischer, M., Lang, Y., Bluethmann, H., Lipp, H.-P., DeArmond, S. J., Prusiner, S. B., Aguet, M., and Weissmann, C. (1992). Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature 356:577–582.

    Google Scholar 

  • Büeler, H., Aguzzi, A., Sailer, A., Greiner, R.-A., Autenried, P., Aguet, M., and Weissmann, C. (1993). Mice devoid of PrP are resistant to scrapie. Cell 73:1339–1347.

    Google Scholar 

  • Büeler, H., Raeber, A., Sailer, A., Fischer, M., Aguzzi, A., and Weissmann, C. (1994). High prion and PrPSc levels but delayed onset of disease in scrapie-inoculated mice heterozygous for a disrupted PrP gene. Mol. Med. 1:19–30.

    Google Scholar 

  • Chandler, R. L. (1961). Encephalopathy in mice produced by inoculation with scrapie brain material. Lancet 1:1378–1379.

    Google Scholar 

  • Chesebro, B., and Caughey, B. (1993). Scrapie agent replication without the prion protein? Curr. Biol. 3:696–698.

    Google Scholar 

  • Collinge, J., Owen, F., Poulter, M., Leach, M., Crow, T. J., Rossor, M. N., Hardy, J., Mulian, M. J., Janota, I., and Lantos, P. L. (1990). Prion dementia without characteristic pathology. Lancet 336:7–9.

    Google Scholar 

  • Collinge, J., Whittington, M. A., Sidle, K. C. L., Smith, C. J., Palmer, M. S., Clarke, A. R., and Jefferys, J. G. R. (1994). Prion protein is necessary for normal synaptic function. Nature 370:295–297.

    Google Scholar 

  • DeArmond, S. J., Mobley, W. C., DeMott, D. L., Barry, R. A., Beckstead, J. H., and Prusiner, S. B. (1987). Changes in the localization of brain prion proteins during scrapie infection. Neurology 37, 1271–1281.

    Google Scholar 

  • Forloni, G., Angeretti, N., Chiesa, R., Monzani, E., Salmona, M., Bugiani, O., and Tagliavini, F. (1993). Neurotoxicity of a prion protein fragment. Nature 362:543–546.

    Google Scholar 

  • Gajdusek, D. C., Gibbs, C. J., and Alper, M. (1966). Experimental transmission of a kuru-like syndrome to chimpanzees. Nature (London) 209:794–796.

    Google Scholar 

  • Gibbs, C. J., Jr., Gajdusek, D. C., Asher, D. M., Alper, M. P., Beck, E., Daniel, P. M., and Matthews, W. B. (1968). Creutzfeldt-Jakob disease (spongiform encephalopathy): Transmission to the chimpanzee. Science 161:388–389.

    Google Scholar 

  • Goldmann, W., Hunter, N., Martin, T., Dawson, M., and Hope, J. (1991). Different forms of the bovine PrP gene have five or six copies of a short G-C-rich element within the protein-coding exon. J. Gen. Virol. 72:201–204.

    Google Scholar 

  • Harada, A., Oguchi, K., Okabe, S., Kuno, J., Terada, S., Ohsima, T., Sato-Yoshitake, R., Takei, Y., Noda, T., and Hirokawa, N. (1994). Altered microtubule organization in small-calibre axons of mice lacking tau protein. Nature 369:488–491.

    Google Scholar 

  • Harris, D. A., Falls, D. L., Johnson, F. A., and Fischbach, G. D. (1991). A prion-like protein from chicken brain copurifies with an acetylcholine receptor-inducing activity. Proc. Natl. Acad. Sci. USA 88:7664–7668.

    Google Scholar 

  • Hsiao, K., Scott, K. M., Foster, D., Groth, D. F., DeArmond, S. J., and Prusiner, S. B. (1990). Spontaneous neurodegeneration in transgenic mice with mutant prion protein. Science 250:1587–1590.

    Google Scholar 

  • Ito, M. (1984). The Cerebellum and Neural Control, Raven, New York.

    Google Scholar 

  • Kano, M., Kato, M., and Chang, H. S. (1988). The glutamate receptor subtype mediating parallel fibre-Purkinje cell transmission in rabbit cerebellar cortex. Neurosci. Res. 5:325–337.

    Google Scholar 

  • Kimberlin, R. H., and Walker, C. A. (1978). Evidence that the transmission of one source of scrapie agent to hamsters involves separation of agent strains from a mixture. J. Gen. Virol. 39:487–496.

    Google Scholar 

  • Kocisco, D. A., Come, J. H., Priola, S. A., Chesebro, B., Raymond, G. J., Lansbury, P. T., and Caughey, B. (1994). Cell-free formation of protease-resistant prion protein. Nature 370:471–474.

    Google Scholar 

  • Li, E., Bestor, T. H., and Jaenisch, R. (1992). Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69:915–926.

    Google Scholar 

  • Loche, C., Chesebro, B., Race, R., and Keith, J. M. (1986). Molecular cloning and complete sequence of prion protein cDNA from mouse brain infected with scrapie agent. Proc. Natl. Acad. Sci. USA 83:6372–6376.

    Google Scholar 

  • Manson, J., West, J. D., Thomson, V., McBride, P., Kaufman, M. H., and Hope, J. (1993). The prion protein gene: A role in mouse embryogenesis? Development 115:117–122.

    Google Scholar 

  • Manson J. C., Clarke, A. R., Hooper, M. L., Aitchison, L., McConnell, I., and Hope, J. (1994a). 129/Ola mice carrying a null mutation in PrP that abolishes mRNA production are developmentally normal. Mol. Neurobiol. 8:121–127.

    Google Scholar 

  • Manson, J. C., Clarke, A. R., McBride, P. A., McConnell, I., and Hope, J. (1994b). PrP gene dosage determines the timing but not the final intensity or distribution of lesions in scrapie pathology. Neurodegeneration 3:331–340.

    Google Scholar 

  • Manuelidis, E. E., Angelo, J. N., Gorgacz, E. J., and Manuelidis, L. (1977). Transmission of Creutzfeldt-Jacob disease to Syrian hamster. Lancet 1:479.

    Google Scholar 

  • Mattson, M. P. (1990). Antigenic changes similar to those seen in neurofibrillary tangles are elicited by glutamate and Ca2- influx in cultured hippocampal neurons. Neuron 4:105–117.

    Google Scholar 

  • Mattson, M. P., Barger, S. W., Cheng, B., Lieberburg, I., Smith-Swintosky, V. L., and Rydel, R. E. (1993). β-Amyloid precursor protein metabolites and loss of neuronal Ca2+ homeostasis in Alzheimer disease. Trends Neurosci. 16:409–414.

    Google Scholar 

  • McKinley, M. P., Bolton, D. C., and Prusiner, S. B. (1983). A protease-resistant protein is a structural component of the scrapie prion. Cell 35:57–62.

    Google Scholar 

  • McMahon, A. P., and Bradley, A. (1990). The Wnt-1 (int-1) proto-oncogene is required for development of a large region of the mouse brain. Cell 62:1073–1085.

    Google Scholar 

  • Oesch, B., Westaway, D., Wälchli, M., McKinley, M. P., Kent, S. B. H., Aebersold, R., Barry, R. A., Tempst, P., Teplow, D. B., Hood, L. E., Prusiner, S. B., and Weissmann, C. (1985). A cellular gene encodes scrapie PrP 27–30 protein. Cell 40:735–746.

    Google Scholar 

  • Prusiner, S. B. (1982). Novel proteinaceous infectious particles cause scrapie. Science 216:136–144.

    Google Scholar 

  • Prusiner, S. B. (1994). Biology and genetics of prion diseases. Annu. Rev. Microbiol. 48:655–686.

    Google Scholar 

  • Prusiner, S. B., Groth, D. F., Bolton, D. C., Kent, S. B., and Hood, L. E. (1984). Purification and structural studies of a major scrapie prion protein. Cell 38:127–134.

    Google Scholar 

  • Prusiner, S. B., Groth, D., Serban, A., Koehler, R., Foster, D., Torchia, M., Burton, D., Yang, S.-L., and DeArmond, S. J. (1993). Ablation of the prion protein (PrP) gene in mice prevents scrapie and facilitates production of anti-PrP antibodies. Proc. Natl. Acad. Sci. USA 90:10608–10612.

    Google Scholar 

  • Puckett, C., Concannon, P., Casey, C., and Hood, L. (1991). Genomic structure of the human prion protein gene. Am J. Hum. Genet. 49:320–329.

    Google Scholar 

  • Rudnicki, M. A., Braun, T., Hinuma, S., and Jeanisch, R. (1992). Inactivation of MyoD in mice leads to up-regulation of myogenic HLA gene Myf-5 and results in apparently normal muscle development. Cell 71:383–390.

    Google Scholar 

  • Sailer, A., Büeler, H., Fischer, M., Aguzzi, A., and Weissmann, C. (1994). No propagation of prions in mice devoid of PrP. Cell 77:967–968.

    Google Scholar 

  • Sakaguchi, S., Katamine, S., Yamanouchi, K., Kishikawa, M., Moriuchi, R., Yasukawa, N., Doi, T., and Miyamoto, T. (1993). Kinetics of infectivity are dissociated from PrP accumulation in salivary glands of Creutzfeldt-Jakob disease agent-inoculated mice. J. Gen. Virol. 74:2117–2123.

    Google Scholar 

  • Sakaguchi, S., Katamine, S., Shigematsu, K., Nakatani, A., Moriuchi, R., Nishida, N., Kurokawa, K., Nakaoke, R., Sato, H., Jishage, K., Kuno, J., Noda, T., and Miyamoto, T. (1995). Accumulation of proteinase K-resistant prion protein is restricted by the expression level of normal PrP in mice inoculated with a mouse-adapted strain of the Creutzfeldt-Jakob disease agent. J. Virol. 69:7586–7592.

    Google Scholar 

  • Sakaguchi, S., Katamine, S., Nishida, N., Moriuchi, R., Shigematsu, K., Sugimoto, T., Nakatani, A., Kataoka, Y., Houtani, T., Shirabe, S., Okada, H., Hasegawa, S., Miyamoto, T., and Noda, T. (1996). Loss of cerebellar Purkinje cells in aged mice homozygous for disrupted PrP gene. Nature 380:528–531.

    Google Scholar 

  • Sakurai, M. (1990). Calcium is an intracellular mediator of the climbing fiber in induction of cerebellar long-term depression. Proc. Natl. Acad. Sci. USA 87:3383–3385.

    Google Scholar 

  • Shehee, W. R., Oliver, P., and Smithies, O. (1993). Lethal thalassemia after insertional disruption of the mouse major adult β-globin gene. Proc. Natl. Acad. Sci. USA 90:3177–3181.

    Google Scholar 

  • Shinagawa, M., Munekata, E., Doi, S., Takahashi, K., Goto, H., and Sato, G. (1986). Immunoreactivity of synthetic pentapeptide corresponding to the N-terminal region of the scrapie prion protein. J. Gen. Virol. 67:1745–1750.

    Google Scholar 

  • Smithies, O., and Maeda, N. (1995). Gene targeting approaches to complex genetic diseases: Atherosclerosis and essential hypertension. Proc. Natl. Acad. Sci. USA 92:5266–5272.

    Google Scholar 

  • Stahl, N., Borchet, D. R., Hsiao, K., and Prusiner, S. B. (1987). Scrapie prion protein contains a phosphatidylinositol glycolipid. Cell 51:229–240.

    Google Scholar 

  • Takeshima, H., Iino, M., Takekura, H., Nishi, M., Kuno, J., Minowa, O., Takeno, H., and Noda, T. (1994). Excitation-contraction uncoupling and muscular degeneration in mice lacking functional skeletal muscle ryanodine-receptor gene. Nature 369:556–559.

    Google Scholar 

  • Tateishi, J., Ohta, M., Soga, M., Sato, Y., and Kuroiwa, Y. (1979). Transmission of chronic spongiform encephalopathy with kuru plaques from humans to rodents. Ann. Neurol. 5:581–584.

    Google Scholar 

  • Uehara, Y., Minowa, O., Mori, C., Shiota, K., Kuno, J., Noda, T., and Kitamura, N. (1995). Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor. Nature 373:702–705.

    Google Scholar 

  • Weissmann, C. (1991). A “unified theory” of prion propagation. Nature 352:679–683.

    Google Scholar 

  • Westaway, D., and Prusiner, S. B. (1986). Conservation of the cellular gene encoding the scrapie prion protein. Nucleic Acids Res. 14:2035–2044.

    Google Scholar 

  • Whittington, M. A., Sidle, K. C. L. S., Gowland, I., Meads, J., Hill, A. F., Palmer, M. S., Jefferys, J. G. R., and Collinge, J. (1995). Rescue of neurophysiological phenotype seen in PrP null mice by transgene encoding human prion protein. Nat. Genet. 9:197–201.

    Google Scholar 

  • Xi, Y. G., Ingrosso, L., Ladogana, A., Masullo, C., and Pocchiari, M. (1992). Amphotericin B treatment dissociates in vivo replication of the scrapie agent from PrP accumulation. Nature 356:598–601.

    Google Scholar 

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Authors and Affiliations

  1. Department of Bacteriology, Nagasaki University School of Medicine, 1-12-4 Sakamoto, Nagasaki, 852, Japan

    Shigeru Katamine, Noriyuki Nishida, Suehiro Sakaguchi, Akira Nakatani, Sumitaka Hasegawa, Ryozo Moriuchi & Tsutomu Miyamoto

  2. Department of Anatomy, Kansai Medical University, Moriguchi, 570, Japan

    Tetsuo Sugimoto

  3. Department of Cell Biology, Cancer Institute, Tokyo, 170, Japan

    Tetsuo Noda

  4. Department of Pathology, Nagasaki University School of Medicine, 1-12-4 Sakamoto, Nagasaki, 852, Japan

    Kazuto Shigematsu

  5. Department of Hospital Pharmacy, Faculty of Medicine, Kyushu University, Fukuoka, 812, Japan

    Yasufumi Kataoka

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  1. Shigeru Katamine
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  2. Noriyuki Nishida
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  3. Tetsuo Sugimoto
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Katamine, S., Nishida, N., Sugimoto, T. et al. Impaired Motor Coordination in Mice Lacking Prion Protein. Cell Mol Neurobiol 18, 731–742 (1998). https://doi.org/10.1023/A:1020698305911

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