Progress and problems in the biology, diagnostics, and therapeutics of prion diseases

Abstract

The term "prion" was introduced by Stanley Prusiner in 1982 to describe the atypical infectious agent that causes transmissible spongiform encephalopathies, a group of infectious neurodegenerative diseases that include scrapie in sheep, Creutzfeldt-Jakob disease in humans, chronic wasting disease in cervids, and bovine spongiform encephalopathy in cattle. Over the past twenty years, the word "prion" has been taken to signify various subtly different concepts. In this article, we refer to the prion as the transmissible principle underlying prion diseases, without necessarily implying any specific biochemical or structural identity. When Prusiner started his seminal work, the study of transmissible spongiform encephalopathies was undertaken by only a handful of scientists. Since that time, the "mad cow" crisis has put prion diseases on the agenda of both politicians and the media. Significant progress has been made in prion disease research, and many aspects of prion pathogenesis are now understood. And yet the diagnostic procedures available for prion diseases are not nearly as sensitive as they ought to be, and no therapeutic intervention has been shown to reliably affect the course of the diseases. This article reviews recent progress in the areas of pathogenesis of, diagnostics of, and therapy for prion diseases and highlights some conspicuous problems that remain to be addressed in each of these fields.

Figure 1

Models of PrP^C to PrP^Sc conversion. (A) The heterodimer model proposes that upon infection of an appropriate host cell, the incoming PrP^Sc (orange) starts a catalytic cascade using PrP^C (blue) or a partially unfolded intermediate arising from stochastic fluctuations in PrP^C conformations as a substrate, converting it by a conformational change into a new β-sheet–rich protein. The newly formed PrP^Sc (green-orange) will in turn convert new PrP^C molecules. (B) The noncatalytic nucleated polymerization model proposes that the conformational change of PrP^C into PrP^Sc is thermodynamically controlled: the conversion of PrP^C to PrP^Sc is a reversible process but at equilibrium strongly favors the conformation of PrP^C. Converted PrP^Sc is established only when it adds onto a fibril-like seed or aggregate of PrP^Sc. Once a seed is present, further monomer addition is accelerated.

Figure 2

Positioning of FDCs in spleens of WT and CXCR5^–/– mice. (A and B) Diagrammatic representation of white pulp follicles in prion-infected CXCR5^–/– and WT mice. Anti-CD21 immunostaining was performed to visualize the lymphoid white pulp follicle microarchitecture. (C) Atypically localized perivascular FDCs in lymph follicles in CXCR5^–/– mice. Sympathetic nerves, visualized with antibodies to tyrosine hydroxylase (TH), are in close vicinity to FDCs (visualized by FDC-M1 immunostaining) (D). Scale bar: 50 mm. In contrast, sympathetic nerves in WT FDCs are localized in B cell areas at the periphery of the follicles (E and F). Arrowheads indicate TH and FDC-M1 positive areas. (G) Sympathetic nerves lining the thoracic spinal cord connect lymphoid organs and the CNS. (H) Shortened prion disease incubation period in CXCR5^–/– mice inoculated intraperitoneally, relative to WT controls.