Prion diseases can be infectious, sporadic and genetic1,2,3,4. The infectious forms of these diseases, including bovine spongiform encephalopathy and Creutzfeldt-Jakob disease, are usually characterized by the accumulation in the brain of the transmissible pathogen, an abnormally folded isoform of the prion protein (PrP) termed PrPSc. However, certain inherited PrP mutations appear to cause neurodegeneration in the absence of PrPSc (refs 5,6,7,8), working instead by favoured synthesis of CtmPrP, a transmembrane form of PrP (ref. 9). The relationship between the neurodegeneration seen in transmissible prion diseases involving PrPSc and that associated with CtmPrP has remained unclear. Here we find that the effectiveness of accumulated PrPSc in causing neurodegenerative disease depends upon the predilection of host-encoded PrP to be made in the CtmPrP form. Furthermore, the time course of PrPSc accumulation in transmissible prion disease is followed closely by increased generation of CtmPrP. Thus, the accumulation of PrPSc appears to modulate in trans the events involved in generating or metabolising CtmPrP. Together, these data suggest that the events of CtmPrP-mediated neurodegeneration may represent a common step in the pathogenesis of genetic and infectious prion diseases.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Prusiner,S. B. Prions. Proc. Natl Acad. Sci. USA 95, 13363–13383 (1998).
Weissmann,C. Molecular genetics of transmissible spongiform encephalopathies. J. Biol. Chem. 274, 3–6 (1999).
Johnson,R. T. & Gibbs,C. J. Jr Creutzfeldt-Jakob disease and related transmissible spongiform encephalopathies. New Eng. J. Med. 399, 1994–2004 (1998).
Horwich,A. L. & Weissman,J. S. Deadly conformations—protein misfolding in prion disease. Cell 89, 499–510 (1997).
Brown,P. et al. Human spongiform encephalopathy: the National Institutes of Health series of 300 cases of experimentally transmitted disease. Ann. Neurol. 35, 513–529 (1994).
Tateishi,J. et al. Immunochemical, molecular genetic, and transmission studies on a case of Gerstmann-Straussler-Scheinker syndrome. Neurology 40, 1578–1581 (1990).
Tateishi,J., Kitamoto,T., Hoque,M. Z. & Furukawa,H. Experimental transmission of Creutzfeldt-Jakob disease and related disorders to rodents. Neurology 46, 532–537 (1996).
Tateishi,J. & Kitamoto,T. Inherited prion diseases and transmission to rodents. Brain Path. 5, 53–59 (1995).
Hegde,R. S. et al. A transmembrane form of the prion protein in neurodegenerative disease. Science 279, 827–834 (1998).
Manson,J. C., Clarke,A. R., McBride,P. A., McConnell,I. & Hope,J. PrP gene dosage determines the timing but not the final intensity or distribution of lesions in scrapie pathology. Neurodegeneration 3, 331–340 (1994).
Meyer,R. K. et al. Separation and properties of cellular and scrapie prion proteins. Proc. Natl Acad. Sci. USA 83, 2310–2314 (1986).
Czub,M., Braig,H. R. & Diringer,H. Pathogenesis of scrapie: study of the temporal development of clinical symptoms, of infectivity titres and scrapie-associated fibrils in brains of hamsters infected intraperitoneally. J. Gen. Virol. 67, 2005–2009 (1986).
Prusiner,S. B. Transgenetic studies implicate interactions between homologous PrP isoforms in scrapie prion replication. Cell 63, 673–686 (1990).
Pattison,I. H. & Jones,K. M. Modification of a strain of mouse-adapted scrapie by passage through rats. Res. Vet. Sci. 9, 408–410 (1968).
Kascsak,R. J. et al. Mouse polyclonal and monoclonal antibody to scrapie-associated fibril proteins. J. Virol. 61, 3688–3693.
Spudich,S. et al. Complete penetrance of Creutzfeldt-Jakob disease in Libyan Jews carrying the E200K mutation in the prion protein gene. Mol. Med. 1, 607–613 (1995).
Gabizon,R. et al. Insoluble wild-type and protease-resistant mutant prion protein in brains of patients with inherited prion disease. Nature Med. 2, 59–64 (1996).
Tranchant,C. et al. Gerstmann-Straussler-Scheinker disease in an Alsation family: clinical and genetic studies. J. Neurol. Neurosurg. Psych. 55, 185–187 (1992).
Sidrauski,C., Chapman,R. & Walter,P. The unfolded protein response: an intracellular signalling pathway with many surprising features. Trends Cell Biol. 8, 245–249 (1998).
Hammond,C. & Helenius,A. Quality control in the secretory pathway. Curr. Opin. Cell Biol. 7, 523–529 (1995).
Hegde,R. S., Voigt,S. & Lingappa,V. R. Regulation of protein topology by trans-acting factors at the endoplasmic reticulum. Mol. Cell 2, 85–91 (1998).
Lopez,C. D., Yost,C. S., Prusiner,S. B., Myers,R. M. & Lingappa,V. R. Unusual topogenic sequence directs prion protein biogenesis. Science 248, 226–229 (1990).
Tatzelt,J. et al. Scrapie prions selectively modify the stress response in neuroblastoma cells. Proc. Natl. Acad. Sci. USA 92, 2944–2948 (1995).
Wong,K. et al. Decreased receptor-mediated calcium response in prion-infected cells correlates with decreased membrane fluidity and IP3 release. Neurology 47, 741–750 (1996).
Johnston,A. R., Fraser,J. R., Jeffery,M. & MacLeod,N. Synaptic plasticity in the CA1 area of the hippocampus of scrapie-infected mice. Neurobiol. Dis. 5, 188–195 (1998).
Serban,D., Taraboulous,A., DeArmond,S. J. & Prusiner,S. B. Rapid detection of Creutzfeldt-Jakob disease and scrapie prion proteins. Neurology 40, 110–117 (1990).
Barry,R. A. & Prusiner,S. B. Monoclonal antibodies to the cellular and scrapie prion protein. J. Infect. Dis. 154, 518–521 (1986).
Telling,G. C. et al. Interactions between wild-type and mutant prion proteins modulate neurodegeneration in transgenic mice. Genes Dev. 10, 1736–1750 (1996).
Marsh,R. F. & Kimberlin,R. H. Comparison of scrapie and transmissible mink encephalopathy in hamsters. II. Clinical signs, pathology, and pathogenesis. J. Infect. Dis. 131, 104–110 (1975).
Chandler,R. L. Encephalopathy in mice produced by inoculation with scrapie brain material. Lancet 1, 1378–1379 (1961).
We are grateful to C. Petromilli and C. Cruz for animal care, A. Calayag and M. Zimmerman for technical assistance, J. Cayeteno for assistance with neuropathology, and T. Rutkowski, N. Shah and S. Mitra for discussions and comments on this manuscript.
About this article
Cite this article
Hegde, R., Tremblay, P., Groth, D. et al. Transmissible and genetic prion diseases share a common pathway of neurodegeneration. Nature 402, 822–826 (1999) doi:10.1038/45574
Journal of Peptide Science (2019)
Molecular Neurobiology (2018)
A novel Gerstmann-Sträussler-Scheinker disease mutation defines a precursor for amyloidogenic 8 kDa PrP fragments and reveals N-terminal structural changes shared by other GSS alleles
PLOS Pathogens (2018)
MGRN1-mediated ubiquitination of α -tubulin regulates microtubule dynamics and intracellular transport