Molecular Pathology of the Prions

What Would Thomas Henry Huxley Have Made of Prion Diseases?

Introduction "Science is nothing but trained and organized common sense, differing from the latter only as a veteran may differ from a raw recruit. "a Prion disease is a disease of the second half of the twentieth century, but the scientific method that has elucidated this fascinating group of diseases is much older. As an […]

Prion Protein as Copper-Binding Protein at the Synapse

Introduction Various approaches have been taken to study the function of prion proteins. Biochemical methods were applied to search for a binding partner of PrPC which is attached to the cell surface by a glycosylphosphatidylinositol GPI anchor (1). The glial fibrillary acidic protein was one of the first possible binding partners to be described (2) […]

A Function for the Prion Protein?

Introduction Protein function is often observed directly following protein isolation, or is deduced by loss of function following gene knockout or by analogy with proteins of known function and similar amino acid sequence. None of these is true in the case of prion proteins because aside from the association with the pathogenesis of the spongiform […]

Prion Protein Peptide Part 1

Introduction The fundamental problem in addressing prion diseases, or the transmissible spongiform encephalopathies, is finding an explanation for the massive neu-ronal death that occurs. Although some understanding of the mechanism by which neuronal death occurs comes from studies with scrapie-infected mice, most of the insights regarding a possible mechanism have come from cell culture models […]

Prion Protein Peptide Part 2

Loss of Function Despite the clear role of glia in cell culture models of PrP106-126 toxicity, the foregoing discussion indicates that glial effects, although necessary, are not sufficient for induction of neuronal loss. The foremost indication for this is the necessity for PrPC expression. Neither PrP106-126 nor PrPSc was toxic to cultures of cerebellar cells […]

Characterization of Bovine Spongiform Encephalopathy and Scrapie Strains/Isolates by Immunochemical Analysis of PrPSc

Introduction In the past two decades, thoroughly standardized mouse incubation time and brain lesion profile scoring assays have been developed to discriminate between prion strains. However, in these mouse infection experiments, large numbers of animals (about 20 mice/line) from three different highly inbred mouse lines (C57Bl, VM95, RIII), plus their intercrosses, need to be infected, […]

Differential Targeting of Neurons by Prion Strains Part 1

Introduction A basic principle of microbiology that applies to all conventional infectious pathogens is that the disease phenotype is a function of both the infecting agent and the host’s response to it. All evidence indicates that this principle is also true for diseases acquired by infection with prions, given that inoculation of different scrapie prion […]

Differential Targeting of Neurons by Prion Strains Part 2

PrPC Glycoform Heterogeneity as a Function of Brain Region To explain selective targeting of different neuronal populations by prion strain, we hypothesized that there are cell-specific differences in the affinity of an infecting PrPSc for PrPC, which in turn determines brain region differences in the rate of nascent PrPSc formation and accumulation. From the evidence […]

Transgenic Studies of Prion Diseases

Introduction This topic reviews studies that involve the manipulation of prion protein (PrP) genes by transgenesis in mice. These consist of two approaches: PrP gene knockout and gene replacement using homologous recombination in embryonic stem cells; and microinjection of transgenes into fertilized embryos. These studies have provided important insights into the pathogenesis of prion diseases […]

Prions: From Neurografts to Neuroinvasion

Introduction The prion hypothesis states that the partially protease-resistant and detergent-insoluble prion protein (PrPSc) is identical with the infectious agent, and lacks any detectable nucleic acids. Since the latter discovery, transgenic mice have contributed many important insights to the field of prion biology. The prion protein (PrPC) is encoded by the Prnp gene, and disruption […]

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