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

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.Prion pathogenesis, diagnostics, and therapy: where do we stand?Prion diseases, also known as transmissible spongiform encephalopathies (TSEs), are invariably fatal neurodegenerative disorders affecting a broad spectrum of host species and arise via genetic, infectious, or sporadic mechanisms (Table 1).In humans, prion diseases result from infectious modes of transmission (variant Creutzfeldt-Jakob disease [vCJD], iatrogenic CJD, Kuru); inherited modes of transmission in which there is nonconservative germ line mutation of the PRNP gene open reading frame (familial CJD, Gerstmann-Sträussler-Scheinker Syndrome, Fatal Familial Insomnia) (1, 2); and modes of transmission that have as yet been neither determined nor understood (sporadic CJD [sCJD]).The clinical symptoms associated with each of the human prion disease forms vary dramatically (2).Nomenclature applied to prion biology continues to be complex and confusing to nonspecialists.Here we utilize the term "prion" to denote the causative agent of prion diseases, without implying associated structural properties.We refer to the disease-associated prion protein (PrP Sc ), a disease-specific isoform of the host-encod- Progress in understanding prion pathogenesis Prion pathogenesis is a dynamic process that can be broken down into spatially and temporally distinct phases: (a) infection andThe Science in medicine series is supported in part by a generous grant from the Doris Duke Charitable Foundation.Nonstandard abbreviations used: bovine spongiform encephalopathy (BSE); cellular prion protein (PrP C ); Creutzfeldt-Jakob disease (CJD); C-terminal transmembrane PrP ( Ctm PrP); CXC chemokine receptor 5 (CXCR5); cytidyl-guanyl oligodeoxynucleotide (CpG-ODN); days post-inoculation (dpi); disease-associated prion protein (PrP Sc ); erythroid differentiation-related factor (EDRF); follicular dendritic cell (FDC); LTβ receptor immunoglobulin fusion protein (LTβR-Ig); lymphoreticular system (LRS); lymphotoxin (LT); Prnp knockout (Prnp o/o ); Rocky Mountain Laboratory (RML); sporadic Creutzfeldt-Jakob disease (sCJD); toll-like receptor 9 (TLR9); transmissible spongiform encephalopathy (TSE); tyrosine-tyrosine-arginine (YYR); variant Creutzfeldt-Jakob disease (vCJD). Conflict of interest:The authors have declared that no conflict of interest exists.