Mapping the parameters of prion-induced neuropathology.

We present a theoretical framework that enables us to dissect out the parametric dependencies of the pathogenesis of prion diseases. We are able to determine the influence of both host-dependent factors (connectivity, cell density, protein synthesis rate, and cell death) and strain-dependent factors (cell tropism, virulence, and replication rate). We use a model based on a linked system of differential equations on a lattice to explore how the regional distribution of central nervous system pathology in Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome, and fatal familial insomnia relates to each of these factors. The model then is used to make qualitative predictions about the pathology for two possible hypothetical triggers of neuronal loss in prion diseases. Pathological progression in overexpressing mouse models has been shown to depend on the site of initial infection. The model allows us to compare the pathologies resulting from different inoculation routes.

[1]  S. Prusiner.  Novel proteinaceous infectious particles cause scrapie. , 1982, Science.

[2]  A. Aguzzi,et al.  Transgenic and Knockout Mice in Research on Prion Diseases , 1998, Brain pathology.

[3]  J. Griffith,et al.  Nature of the Scrapie Agent: Self-replication and Scrapie , 1967, Nature.

[4]  H. Fraser,et al.  Enucleation after intraocular scrapie injection delays the spread of infection , 1989, Brain Research.

[5]  S. Prusiner,et al.  The neuropathological phenotype in transgenic mice expressing different prion protein constructs. , 1994, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[6]  F. Cohen,et al.  Selective Neuronal Targeting in Prion Disease , 1997, Neuron.

[7]  H. Wiśniewski,et al.  Extensive degeneration of catecholaminergic neurons to scrapie agent 87V in the brains of IM mice. , 1998, Molecular and Chemical Neuropathology.

[8]  H Serban,et al.  Immunologic and molecular biologic studies of prion proteins in bovine spongiform encephalopathy. , 1993, The Journal of infectious diseases.

[9]  P Brown,et al.  Classification of sporadic Creutzfeldt‐Jakob disease based on molecular and phenotypic analysis of 300 subjects , 1999, Annals of neurology.

[10]  M A Nowak,et al.  Quantifying the kinetic parameters of prion replication. , 1999, Biophysical chemistry.

[11]  G. Forloni,et al.  Prion protein fragment 106–126 induces apoptotic cell death and impairment of L‐type voltage‐sensitive calcium channel activity in the GH3 cell line , 1998, Journal of neuroscience research.

[12]  M. Royston,et al.  Synaptic degeneration is the primary neuropathological feature in prion disease: a preliminary study. , 1993, Neuroreport.

[13]  S. Prusiner,et al.  Ablation of the prion protein (PrP) gene in mice prevents scrapie and facilitates production of anti-PrP antibodies. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[14]  A. Giese,et al.  Neuronal Cell Death in Scrapie‐Infected Mice Is Due to Apoptosis , 1995, Brain pathology.

[15]  S. Itohara,et al.  Prions prevent neuronal cell-line death , 1999, Nature.

[16]  A. Aguzzi,et al.  Prion research: the next frontiers , 1997, Nature.

[17]  David C. Krakauer,et al.  The spatial dynamics of prion disease , 1998, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[18]  S. Prusiner,et al.  Prion Protein Transgenes and the Neuropathology in Prion Diseases , 1995, Brain pathology.

[19]  B. Kagan,et al.  Channel Formation by a Neurotoxic Prion Protein Fragment* , 1997, The Journal of Biological Chemistry.

[20]  J. Bell,et al.  Neuropathology of spongiform encephalopathies in humans. , 1993, British medical bulletin.

[21]  M. Eigen,et al.  Prionics or the kinetic basis of prion diseases. , 1996, Biophysical chemistry.

[22]  S. Prusiner,et al.  A hypothalamic neuronal cell line persistently infected with scrapie prions exhibits apoptosis , 1997, Journal of virology.

[23]  Martin A. Nowak,et al.  Prion infection dynamics , 1998 .

[24]  P. Liberski,et al.  Severe, Early and Selective Loss of a Subpopulation of GABAergic Inhibitory Neurons in Experimental Transmissible Spongiform Encephalopathies , 1998, Brain pathology.

[25]  M. Bruce,et al.  Scrapie strain variation and mutation. , 1993, British medical bulletin.

[26]  J. Hauw,et al.  Strain specific and common pathogenic events in murine models of scrapie and bovine spongiform encephalopathy. , 1996, The Journal of general virology.