Disease aetiology of each brain sample is designated above each lane and the PrPSctype (using the London classification of human PrPSctypes;Collingeet al

Disease aetiology of each brain sample is designated above each lane and the PrPSctype (using the London classification of human PrPSctypes;Collingeet al.1996; Hillet al.2003,2006) andPRNPcodon 129 genotype of the patient (M, methionine; V, valine) are designated below. and other factors may be critical modifiers of the kuru phenotype. Keywords:kuru, prion, spongiform encephalopathy == 1. Introduction == Human prion diseases are fatal neurodegenerative disorders that include CreutzfeldtJakob disease (CJD), GerstmannStrusslerScheinker disease, fatal familial insomnia, kuru and variant CJD (vCJD; Collinge2001,2005;Wadsworth & Collinge 2007). Their central feature is the post-translational conversion Gpm6a of host-encoded, cellular prion protein (PrPC) to an abnormal isoform, designated PrPSc(Prusiner 1982;Collinge 2001). Substantial evidence indicates that an abnormal PrP isoform is the principal, if not the sole, component of the transmissible infectious agent, or prion (Prusiner 1982;Collinge 2001;Weissmann 2004;Collinge & Clarke 2007). Human prion diseases are biologically unique in that the disease process can MARK4 inhibitor 1 be triggered through inherited germ line mutations in the human prion protein gene (PRNP), infection (by inoculation, or in some cases by dietary exposure) with prion-infected tissue or by rare sporadic events that generate PrPSc(Collinge2001,2005;Wadsworthet al.2003;Wadsworth & Collinge 2007). Human prion diseases are associated with a range of clinical presentations and are classified by both clinicopathological syndrome and aetiology with sub-classification according to molecular criteria (Collinge1997,2005;Collinge & Palmer 1997;Wadsworthet al.2003). Approximately 85 per cent of cases occur sporadically as CJD (sporadic CJD) at a rate of 12 cases per million population per year across the world, with an equal incidence in men and women (Brownet al.1987; Collinge2001,2005;Wadsworthet al.2003;Collinset al.2006). Approximately 15 per cent of human prion disease is associated with autosomal dominant pathogenicPRNPmutations and to date over 30 mutations have been described (Collinge2001,2005;Kovacset al.2002;Wadsworthet al.2003;Mead 2006). Iatrogenic forms of prion disease have occurred most frequently due to the transmission of CJD prions via contaminated growth hormone derived from human cadavers, or by implantation of contaminated dura mater grafts (Brownet al.1992,2000). Iatrogenic prion disease has also resulted from transmission of CJD prions during corneal transplantation, contaminated electroencephalographic (EEG) electrode implantation and surgical operations using contaminated instruments or apparatus (Brownet al.1992,2000). Acquired prion disease in humans due to a dietary origin has resulted in kuru, an epidemic prion disease principally of the Fore linguistic group of the Eastern Highlands of Papua New Guinea, which was transmitted during mortuary feasts when deceased relatives were consumed by close MARK4 inhibitor 1 relatives as a mark of respect and mourning (Alpers 1987;Collinge & Palmer 1997;Meadet al.2003), and vCJD in the United Kingdom and other countries caused by human exposure to BSE prions from cattle (Collingeet al.1996;Bruceet al.1997;Hillet al.1997;Collinge 1999;Asanteet al.2002). Kuru demonstrates that incubation periods of infection with human prions can exceed 50 years (Collingeet al.2006) and these data indicate that the parameters of any vCJD epidemic cannot yet be predicted with confidence (Collinge 1999;Froshet al.2004;Hiltonet al.2004;Collingeet al.2006). Human PrP has a common polymorphism at residue 129 (encoding either methionine or valine) and homozygosity confers genetic susceptibility to both sporadic and acquired MARK4 inhibitor 1 forms of CJD (Collingeet al.1991;Palmeret al.1991;Windlet al.1996;Leeet al.2001;Meadet al.2003;Collinset al.2006). The effect of codon 129 is most strikingly observed in vCJD where all clinical cases studied so far have been methionine homozygotes (Collinge 2005;Wadsworth & Collinge 2007). Codon 129 genotype also shows a pronounced effect on kuru incubation periods and susceptibility (Cervenkovet al.1999;Leeet MARK4 inhibitor 1 al.2001;Meadet al.2003;Collingeet al.2006) and the clear survival advantage forPRNPcodon 129 heterozygotes provides a powerful basis for balancing selection in the Fore where the majority of kuru-exposed survivors arePRNP129 heterozygotes (Meadet al.2003). The remarkable degree of clinical and neuropathological heterogeneity observed across the spectrum of human prion disease has yet to be fully explained. However, it has MARK4 inhibitor 1 been clear for many years that distinct isolates, or strains, of prions can be propagated in the same host and these are biologically recognized by distinctive clinical and pathological features in inoculated laboratory animals (Collinge 2001;Hill & Collinge 2001;Bruce 2003;Collinge & Clarke 2007). It is therefore probable that a significant proportion of clinicopathological heterogeneity seen in human prion diseases relates to the propagation of distinct human prion strains (Collinge 2001;Collinge & Clarke 2007). Genetic factors also influence prion strain selection through the coding sequence of the host prion protein gene (Collinge1999,2001;Hill & Collinge.