Before Stanley Prusiner discovered prions and coined their name in 1982, the term transmissible spongiform encephalopathy (TSE) had been widely used to represent a group of unique neurodegenerative disorders including scrapie in sheep and goats, chronic wasting disease in elk and deer, bovine spongiform encephalopathy in cattle, and Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker (GSS) syndrome and kuru in humans (1, 2). As indicated by its striking name, a TSE must possess these two major characteristics: transmissibility and spongiform degeneration in the central nervous system (CNS).
The discovery of prions as infectious protein pathogens, which are free of nucleic acids and which are the cause of transmissible spongiform encephalopathies, opened an extraordinary chapter in the history of life science. The protein-only hypothesis maintains that prions are composed entirely of an abnormally shaped prion protein (PrPSc) derived from its normal cellular form (PrPC) via an alpha-helix to beta-sheet structural transition (2). PrPSc has in fact been observed in almost all TSE identified so far. Identification of PrPSc through detection of various protease-resistant PrP core fragments with Western blotting or formic acid-resistant PrP staining with immunohistochemistry has become essential in the current diagnostic criteria for TSE. The designation, “prion diseases”, has largely replaced ”transmissible spongiform encephalopathies,” although co-occurrence of the two terminologies is occasionally seen in recently published literature.
However, confusion results when it is observed that some prion diseases lack one or two characteristics of TSE. For instance, in a large-scale transmission study using nonhuman primates, 10% of sporadic CJD and 32% of familial prion diseases were nontransmissible (3). In addition, it was found that all GSS, except one-third of GSS cases with proline to valine mutation at residue 102 of PrP (P102L), were difficult to transmit to rodents (4). As a result, it has been proposed that CJD and GSS be divided into two groups: (i) readily transmissible, and (ii) difficult to transmit or non-transmissible (4). Further, the spongiform degeneration typical of TSE is not always present in all GSS with P102L mutation, although diffuse deposits of PrPSc plus PrP-amyloid plaques are present in the CNS (5). In transgenic mice expressing murine PrP P101L (equivalent to human P102L) and challenged with GSS free of spongiform degeneration, neither symptoms nor spongiform degeneration was observed despite the presence of PrPamyloid (6). Obviously, conditions such as these, which do not manifest transmissibility, or spongiform degeneration (singly or jointly) should not be considered as types of TSE. They do, however, constitute prion diseases.
Based on a wealth of data gathered so far, one may wonder whether or not prion diseases should now be redefined. Under a reconsidered definition, they should include a group of disorders characterized by the accumulation of abnormal PrP including protease-sensitive and protease-resistant forms in the brain and/or other organs, regardless of the presence of transmissibility and spongiform degeneration. Most importantly, the spectrum of prion diseases must not be restrained by the definition of TSE.
Wen-Quan Zou
Department of Pathology, National Prion Disease Pathology Surveillance Center, Case Western Reserve University, 2085 Adelbert Road, Cleveland, Ohio 44106, USA.
References
1. S. B. Prusiner, Science 216, 136 (1982).
2. S. B. Prusiner, Proc. Natl. Acad. Sci. USA 95, 13363 (1998).
3. P. Brown et al., Ann. Neurol. 35, 513 (1994).
4. J. Tateishi, et al., Neurology 46, 532 (1996).
5. P. Parchi, et al., Proc. Natl. Acad. Sci. USA 95, 8322 (1998).
6. P. Piccardo et al., Proc. Natl. Acad. Sci. USA 104, 4712 (2007).
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