Abstract
Prion diseases are fatal neurodegenerative disorders of humans and animals, which result from the conformational conversion of a normal, cell surface glycoprotein (PrPC) into a pathogenic isoform (PrPSc) that is the main component of infectious prions (1,2) . Familial prion diseases, which include 10% of the cases of Creutzfeldt-Jakob disease and all cases of Gerstmann-Sträussler syndrome and fatal familial insomnia, are linked in an autosomal dominant fashion to point and insertional mutations in the PrP gene on chromosome 20 (3,4). These mutations are presumed to favor spontaneous conversion of PrP to the PrPSc state. One way to experimentally model familial prion diseases is to express PrP molecules carrying disease-associated mutations in either cultured mammalian cells or transgenic mice. The authors review their own work using these two kinds of model systems, which have provided complementary information about the PrPC?PrPSc conversion process, and about the pathogenic effects of mutant PrP.
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References
Prusiner, S. B. (ed.) (1999) Prion Biology and Diseases. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY.
Harris, D. A. (1999) Cellular biology of prion diseases. Clin. Micro. Rev. 12, 429–444.
Young, K., Piccardo, P., Dloughy, S., Bugiani, O., Tagliavini, F., and Ghetti, B. (1999) The human genetic prion diseases. In: Prions: Molecular and Cellular Biology (Harris, D. A., ed.), Horizon Scientific Press, Wymondham. pp 139–175.
Gambetti, P., Petersen, R. B., Parchi, P., Chen, S. G., Capellari, S., Goldfarb, L., et al. (1999) Inherited prion diseases, in Prion Biology and Diseases (Prusiner, S. B., ed.), Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, pp. 509–583.
Lehmann, S. and Harris, D. A. (1996) Mutant and infectious prion proteins display common biochemical properties reminiscent of the scrapie isoform. J. Biol. Chem. 271, 1633–1637.
Lehmann, S. and Harris, D. A. (1996) Two mutant prion proteins expressed in cultured cells acquire biochemical properties reminiscent of the scrapie isoform. Proc. Natl. Acad. Sci. USA 93, 5610–5614.
Lehmann, S. and Harris, D. A. (1997) Blockade of glycosylation promotes acquisition of scrapie-like properties by the prion protein in cultured cells. J. Biol. Chem. 272, 21,479–21,487.
Stahl, N., Baldwin, M. A., Hecker, R., Pan, K.-M., Burlingame, A. L., and Prusiner, S. B. (1992) Glycosylinositol phospholipid anchors of the scrapie and cellular prion proteins contain sialic acid. Biochemistry 31, 5043–5053.
Caughey, B., Neary, K., Buller, R., Ernst, D., Perry, L. L., Chesebro, B., et al. (1990) Normal and scrapie-associated forms of prion protein differ in their sensitivities to phospholipids and proteases in intact neuroblastoma cells. J. Virol. 64, 1093–1101.
Safar, J., Ceroni, M., Gajdusek, D. C., and Gibbs, C. J. (1991) Differences in the membrane interaction of scrapie amyloid precursor proteins in normal and scrapieor Creutzfeldt-Jakob disease-infected brains. J. Infect. Dis. 163, 488–494.
Stahl, N., Borchelt, D. R., and Prusiner, S. B. (1990) Differential release of cellular and scrapie prion proteins from cellular membranes by phosphatidylinositolspecific phospholipase C. Biochemistry 29, 5405–5412.
Lehmann, S. and Harris, D. A. (1995) A mutant prion protein displays an aberrant membrane association when expressed in cultured cells. J. Biol. Chem. 270, 24,589–24,597.
Narwa, R. and Harris, D. A. (1999) Prion proteins carrying pathogenic mutations are resistant to phospholipase cleavage of their glycolipid anchors. Biochemistry 38, 8770–8777.
Hegde, R. S., Mastrianni, J. A., Scott, M. R., DeFea, K. A., Tremblay, P., Torchia, M., et al. (1998) Transmembrane form of the prion protein in neurodegenerative disease. Science 279, 827–834.
Hegde, R. S., Voigt, S., and Lingappa, V. R. (1998) Regulation of protein topology by trans-acting factors at the endoplasmic reticulum. Mol. Cell 2, 85–91.
Hegde, R. S., Tremblay, P., Groth, D., DeArmond, S. J., Prusiner, S. B., and Lingappa, V. R. (1999)Transmissible and genetic prion diseases share a common pathway of neurodegeneration. Nature 402, 822–826.
Stewart, R. S. and Harris, D. A. (1999) A transmembrane form of the prion protein is induced by an artificial mutation, but not by mutations linked to familial prion diseases. Mol. Biol. Cell 10, 414a.
Daude, N., Lehmann, S., and Harris, D. A. (1997) Identification of intermediate steps in the conversion of a mutant prion protein to a scrapie-like form in cultured cells. J. Biol. Chem. 272, 11,604–11,612.
Welch, W. J. and Gambetti, P. (1998) Chaperoning brain diseases. Nature 392, 23–24.
Chiesa, R., Piccardo, P., Ghetti, B., and Harris, D. A. (1998) Neurological illness in transgenic mice expressing a prion protein with an insertional mutation. Neuron 21, 1339–1351.
Chiesa, R., Drisaldi, B., Quaglio, E., Migheli, A., Piccardo, P., Ghetti, B., et al. (2000) Accumulation of protease-resistant PrP and apoptosis of cerebellar granule cells in transgenic mice expressing a prion protein insertional mutation. Submitted.
Owen, F., Poulter, M., Collinge, J., Leach, M., Lofthouse, R., Crow, T. J., et al. (1992) A dementing illness asociated with a novel insertion in the prion protein gene. Mol. Brain Res. 13, 155–157.
Duchen, L. W., Poulter, M., and Harding, A. E. (1993) Dementia associated with a 216 base pair insertion in the prion protein gene. Clinical and neuropathological features. Brain 116, 555–567.
Krasemann, S., Zerr, I., Weber, T., Poser, S., Kretzschmar, H., Hunsmann, G., et al. (1995) Prion disease associated with a novel nine octapeptide repeat insertion in the PRNP gene. Mol. Brain Res. 34, 173–176.
Hsiao, K. K., Scott, 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.
Westaway, D., DeArmond, S. J., Cayetano-Canlas, J., Groth, D., Foster, D., Yang, S.-L., et al. (1994) Degeneration of skeletal muscle, peripheral nerves, and the central nervous system in transgenic mice overexpressing wild-type prion proteins. Cell 76, 117–129.
Muramoto, T., DeArmond, S. J., Scott, M., Telling, G. C., Cohen, F. E., and Prusiner, S. B. (1997) Heritable disorder resembling neuronal storage disease in mice expressing prion protein with deletion of an alpha-helix. Nature Med. 3, 750–755.
Shmerling, D., Hegyi, I., Fischer, M., Blätter, T., Brandner, S., Götz, J., et al. (1998) Expression of amino-terminally truncated PrP in the mouse leading to ataxia and specific cerebellar lesions. Cell 93, 203–214.
Manson, J., West, J. D., Thomson, V., McBride, P., Kaufman, M. H., and Hope, J. (1992) The prion protein gene: a role in mouse embryogenesis? Development 115, 117–122.
Taraboulos, A., Jendroska, K., Serban, D., Yang, S.-L., DeArmond, S. J., and Prusiner, S. B. (1992) Regional mapping of prion proteins in brain. Proc. Natl. Acad. Sci. USA 89, 7620–7624.
Harris, D. A., and Lehmann, S. (1997) Mutant prion proteins acquire PrPSc-like properties in cultured cells: an experimental model of familial prion diseases, in Alzheimer’s Disease: Biology, Diagnosis and Therapeutics (Iqbal, K., Winblad, B., Nishimura, T., Takeda, M., and Wisniewski, H. M., eds.), John Wiley and Sons, Chichester. pp 631–643.
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Harris, D.A., Chiesa, R., Migheli, A., Piccardo, P., Ghetti, B. (2001). Cellular and Transgenic Models of Familial Prion Diseases. In: Baker, H.F. (eds) Molecular Pathology of the Prions. Methods in Molecular Medicineâ„¢, vol 59. Humana Press. https://doi.org/10.1385/1-59259-134-5:149
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DOI: https://doi.org/10.1385/1-59259-134-5:149
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