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Progress and problems in the biology, diagnostics, and therapeutics of prion diseases
Adriano Aguzzi, … , Mathias Heikenwalder, Gino Miele
Adriano Aguzzi, … , Mathias Heikenwalder, Gino Miele
Published July 15, 2004
Citation Information: J Clin Invest. 2004;114(2):153-160. https://doi.org/10.1172/JCI22438.
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Science in Medicine

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

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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.

Authors

Adriano Aguzzi, Mathias Heikenwalder, Gino Miele

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Figure 1

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

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