Journal Article

Insights into prion strains and neurotoxicity

Heikenwalder, Mathias, Aguzzi, Adriano, Polymenidou, Magdalini

2007

Overview

Key Points Transmissible spongiform encephalopathies (TSEs) are neurodegenerative diseases of humans and many animal species that are caused by prions. The main constituent of prions is scrapie prion protein (PrP Sc ), an aggregated moiety of the host-derived membrane glycolipoprotein cellular prion protein (PrP C ). Although PrP C is encoded by the host genome, prions were found to encipher many phenotypic TSE variants, known as prion strains. Prion strains are TSE isolates that, when inoculated into new hosts, consistently cause disease with specific characteristics, such as incubation period, patterns of PrP Sc distribution and relative severity of spongiform changes in the brain (the lesion profile).The agent-specified information of prion strains is thought to be contained within distinct conformations of various PrP Sc isotypes. Prions exert their destructive effects predominantly, if not exclusively, within the central nervous system. However, the direct cause of neurotoxicity remains unclear. PrP C is required for prion replication because mice that lack PrP C are resistant to prions. The presence of PrP C on neurons is a prerequisite for prion-induced neurotoxicity. A series of transgenic mice that express various prion protein mutants indicate that deletion of specific regions of PrP C can render it neurotoxic. This toxicity is modulated by co-expression of wild-type PrP C . Currently, there is no reagent allowing non-invasive, pre-mortem diagnosis of prion diseases. In view of recent unfortunate cases of Creutzfeldt–Jakob disease infection through blood transfusion, reliable, specific and, most importantly, sensitive reagents are urgently needed. Although it is now accepted that the infectious agent that causes transmissible spongiform encephalopathies is PrP Sc , recent insights into the existence of prion strains pose a fascinating challenge to prion research. What is the nature of prion strains? And how can they be discriminated? Transmissible spongiform encephalopathies (TSEs) are neurodegenerative diseases that are caused by prions and affect humans and many animal species. It is now widely accepted that the infectious agent that causes TSEs is PrP Sc , an aggregated moiety of the host-derived membrane glycolipoprotein PrP C . Although PrP C is encoded by the host genome, prions themselves encipher many phenotypic TSE variants, known as prion strains. Prion strains are TSE isolates that, after inoculation into distinct hosts, cause disease with consistent characteristics, such as incubation period, distinct patterns of PrP Sc distribution and spongiosis and relative severity of the spongiform changes in the brain. The existence of such strains poses a fascinating challenge to prion research.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Amino Acid Sequence / Animal species / Animals / Biochemistry / Biomedical and Life Sciences / Bovine spongiform encephalopathy / Brain - metabolism / Brain - pathology / Cancer Research / Care and treatment / Causes of / Cell Biology / Conserved Sequence / Creutzfeldt-Jakob Syndrome - etiology / Creutzfeldt-Jakob Syndrome - metabolism / Creutzfeldt-Jakob Syndrome - pathology / Developmental Biology / Diagnosis / Disease / Disease Transmission, Infectious / Forecasting / Genetic Variation / Glycosylation / Health aspects / Humans / Hypotheses / Iatrogenesis / Incidence / Life Sciences / Models, Biological / Molecular Sequence Data / Nervous system / Neurotoxicity / Physiological aspects / Prion diseases / Prion Diseases - classification / Prion Diseases - epidemiology / Prion Diseases - etiology / Prion Diseases - pathology / Prion Diseases - transmission / Prion Diseases - veterinary / Prions / Prions - chemistry / Prions - genetics / Prions - metabolism / Prions - pathogenicity / Prions - toxicity / Protein Sorting Signals / Protein Structure, Secondary / Proteins / PrPSc Proteins - chemistry / PrPSc Proteins - genetics / PrPSc Proteins - isolation & purification / PrPSc Proteins - metabolism / PrPSc Proteins - pathogenicity / PrPSc Proteins - toxicity / review-article / Scrapie - pathology / Scrapie - transmission / Sheep / Signal transduction / Species Specificity / Stem Cells / Tissue Distribution