History And Overview

First described in humans in the 1920s, spongiform encephalopathy is now known to encompass a group of noninflammatory degenerative disorders characterized neuropathologically by a diffuse spongiosis and amyloid protein deposition in the brain. These disorders include kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler- Scheinker syndrome (GSS), and fatal familial insomnia (FFI). The report in 1966 that kuru, an epidemic ataxic illness limited to the eastern highlands of Papua New Guinea, could be experimentally transmitted to the chimpanzee [1] opened a new dimension in the study of neurodegenerative disease and led to further experiments using a variety of primates and laboratory rodents. These studies established the transmissible nature of all members of the group that we call the transmissible spongiform encephalopathies (TSE) but are also known as infectious cerebral amyloidoses, or prion diseases. [2] [3] [4

The precise nature of the infectious agents that cause these diseases remains elusive. An early landmark experiment showed that infectivity was not decreased by levels of ionizing irradiation that destroy the biological function of nucleic acid, [5] and this led to a number of hypotheses about non-nucleic acid replication by membrane-complexed polysaccharides or proteins. In the 1980s, the protein hypothesis was bolstered by the demonstration that highly purified brain extracts contained a host-encoded membrane-bound glycoprotein (PrP) that was inseparable from infectivity y ; more recently, mutations in its encoding gene (PRNP) on chromosome 20 have been shown to be linked to familial forms of disease.M

The primary structure of the protein in patients with sporadic and iatrogenic forms of TSE does not differ from that of the protein in healthy individuals. In consequence, the functional differences between the protein in normal and affected individuals--solubility, proteinase resistance, ease of separation from cell membranes, and, most importantly, ability to replicate (infectivity)--are thought to reside in post-translational tertiary or quaternary alterations in protein folding. These have not yet been characterized, and a great deal of discussion surrounds the mechanism by which such alterations could endow the protein with replicative capacity. Two currently popular theories invoke (1) a heterodimer formation of normal and abnormal molecular isoforms that impose a conformational restraint on newly synthesized protein,y and (2) a mineral-induced nucleation of abnormal protein polymer formation akin to that of crystallization. y

The occurrence of spongiform encephalopathy extends well beyond the confines of human medicine. Ever since the early eighteenth century, a spongiform illness called scrapie has been known to affect sheep and goats, and in past decades similar diseases have been identified in mink, cats, and ungulates, most recently as the cause of a dramatic epidemic of spongiform encephalopathy in British cattle. The disease in each of these species appears to have resulted from the contamination of animal feed with meat and bone meal processed from scrapie-infected sheep carcasses, and there is mounting evidence that a small but increasing number of British cases with new variant CJD are due to a further species-jumping transmission to humans, presumably from BSE-contaminated beef products. Apart from these cases, CJD in humans may be broadly categorized as sporadic (for which no evident cause can be determined), familial (associated with mutations in the PRNP gene), and iatrogenic (caused by human-to-human cross-contaminating medical accidents).

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