Diversity of prion diseases: (no) strains attached?

Abstract

Prion diseases are neurodegenerative disorders with a remarkable variability in their clinical presentation, histopathological features and molecular pathology. Prion diseases in humans include (1) sporadic prion disease (sporadic Creutzfeldt-Jakob disease, sCJD), (2) inherited forms of prion diseases (also termed genetic or familial prion disease) such as the Gerstmann–Straussler–Scheinker syndrome (GSS), fatal familial insomnia (FFI) or octapeptide repeat inserts (OPRI) and (3) acquired forms, such as iatrogenic CJD (iCJD), Kuru, and variant CJD (vCJD) [transmission of bovine spongiform encephalopathy (BSE) to humans]. The protein-only hypothesis postulates that the infectious agent, termed ‘‘prion’’ [9], is composed predominantly (if not entirely) of aggregates of misfolded, host-encoded, cellular prion protein (PrP), commonly designated PrP [15]. The partially protease resistant, misfolded (‘‘scrapie’’-) isoform PrP is formed from normal (‘‘cellular’’) host prion protein (PrP) through conformational conversion. The common neuropathological features of prion diseases are a predominantly extracellular accumulation of PrP in the central nervous system. Prion protein deposits can vary considerably in their pattern, distribution and intensity [16, 18]. More than 80% of human prion diseases manifest as sporadic CJD with an incidence of 1–2 cases per million population per year across the world, and are equally frequent in men and women. Ca. 15% of human prion diseases are associated with autosomal dominant pathogenic mutations in the PRNP gene. To date, 37 pathogenic mutations and 19 non-coding polymorphisms have been described [1]. In contrast, acquired human prion diseases are rare: transmission of sCJD prions occurred through treatment with pituitary hormones pooled from human cadavers, transplantation of dura mater or cornea, the use of contaminated EEG electrodes [3], and by cannibalism among the Fore linguistic group in Papua New Guinea [2, 7]. Instead, variant CJD occurred mainly in the UK and in other countries due to human exposure to BSE prions [5], and more recently in a few cases by transmission of vCJD contaminated blood products. A striking phenomenon of prion diseases is the existence of so-called strains. In human sporadic prion disease at least four, possibly a dozen molecular strain types (including subtypes) can be identified. The strain type is related to the clinical phenotype, the histopathological appearance, and the polymorphism on codon 129 of the human prion (PRNP) gene. The molecular strain type is classified by both, fragment size and the ratio of three principal PrP bands seen after limited protease digestion. Importantly, inherited forms show a wide variability of patterns on immunoblots and often do not fit into the scheme that was originally established for sCJD, iCJD and vCJD. The cluster ‘‘prion diseases’’ in this issue of Acta Neuropathologica contains both, review articles and original papers, featuring the relationship of prions with tau, inherited prion diseases, the biology of strains, processing of PrP in the brain and the principle of protein misfolding cyclical amplification (PCMA). Prion diseases share a number of features with other amyloid forming diseases of the CNS, most prominently Alzheimer’s disease, but also other rare conditions such as Familial British Dementia (Worster Drought syndrome). S. Brandner (&) Department of Neurodegenerative Disease and Division of Neuropathology, UCL Institute of Neurology, London WC1N 3BG, UK e-mail: s.brandner@ion.ucl.ac.uk; sebastian.brandner@prion.ucl.ac.uk