Prions were defined by Stanley Prusiner in 1982 as “proteinaceous infectious particles”1. Prion diseases are transmissible, invariably fatal, neurodegenerative disorders that may be inherited, acquired or occur spontaneously as sporadic Creutzfeldt-Jakob disease2. They also affect mammalian species, notably scrapie of sheep, chronic wasting disease of deer and elk3 and bovine spongiform encephalopathy4. Prion diseases arise consequent to misfolding and aggregation of the normal neuronal membrane constituent, prion protein (PrPC), resulting in its conversion to the pathogenic self-propagating conformer, PrPSc – an important event in the initiation and progression of the disease5-7. Thus, PrP exists in two major conformational isoforms: the non-pathogenic, predominantly α-helical, protease-sensitive cellular isoform (PrPC) and the pathogenic, partially protease-resistant scrapie-inducing isoform (PrPSc) that is enriched in β-pleated sheet structure8 – see Figure 1. PrPSc is responsible for prion propagation and constitutes the transmissible agent, able to recruit and convert natively folded PrPC. The current model of prion propagation proposes that PrPSc, either inoculated, or generated as a stochastic event from mutant PrPC (or more rarely from wild-type PrPC), interacts with PrPc and promotes its conformational conversion to PrPSc. This is thought to occur by means of seeded protein polymerisation, a process involving the binding and templated misfolding of normal cellular prion protein, such that PrPSc acts as a template to transfer its conformation onto PrPC, thereby generating new PrPSc 5,7,9. It then follows, that PrP knockout mice do not develop prion disease when challenged with scrapie10-12. PrPSc accumulates in the central nervous system in heterogeneous forms; as amyloid plaques, diffuse deposits and soluble species resulting in progressive neuronal degeneration and neuronal vacuolation5,7,13-14.
Human prion diseases affect approximately 1-1.5 persons per million worldwide annually17. Five subtypes comprise the known prion diseases: Kuru (a disease of the Fore people of Papua New Guinea related to the practice of ritualistic cannibalism of dead relatives as a symbol of respect and mourning18), sporadic Creutzfeldt-Jakob disease (CJD), familial CJD, iatrogenic CJD, Gerstmann-Sträussler-Scheinker syndrome (GSS), Fatal familial insomnia (FFI) and new variant CJD. As a group of disorders, they are unique among neurodegenerative diseases as they not only occur sporadically and are inherited genetically but can also be transmitted horizontally9. According to their aetiology, prion diseases are divided into three groups: (1) diseases acquired through infection by external prions, such is the case of Kuru, caused by consumption of an individual with sporadic CJD19-20, iatrogenic CJD transmitted by medical interventions and variant CJD caused by bovine prions21 (2-5% of CJD cases); (2) disease caused by a genetic mutations in the prion (PRNP) gene, as in the overlapping neurologic syndromes of familial CJD, GSS and FFI (approximately 10-15% of all prion diseases); and (3) sporadic CJD, that constitutes 85-90% of CJD cases and affects 1-1.5 million people per million annually2,14,17,20 (Figure 2)
The transmissible nature of these diseases was first demonstrated experimentally in 1939 by Cuillé and Chelle through intra-ocular administration of scrapie-infected spinal cord to a goat22. Nearly thirty-years later, Kuru, was transmitted to chimpanzees through intra-cerebral inoculation by Gajdusek et al in 196623, and in 1968, Gibbs et al followed suit with intra-cerebral transmission of CJD24. The aetiologic agent of these diseases is now known to be PrPSc 25-27. The classic neuropathology of prion diseases, characterised by accumulation of PrPSc in the central nervous system, comprises spongiform degeneration of the cerebral cortex and subcortical nuclei, astrocytic gliosis, vacuolation and neuronal loss. The disease itself can undergo extraordinarily long incubation periods, however, once clinical onset ensues, the course is often dramatic and relentlessly progressive. The clinically presentation is that of a neurologic or neuropsychiatric condition associated with rapid multi-focal central nervous system degeneration, usually dominated by dementia and cerebellar ataxia7,28.
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