Bovine spongiform encephalopathy in Japan: History and recent studies on oxidative stress in prion diseases

With respect to BSE and vCJD, compliance with the following three rules should strictly be observed: (i) Identification and destruction of all clinically affected cattle; (ii) destruction of all mammalian proteins used in feeding ruminant livestock; and (iii) destruction of all high-risk tissues for use in human consumption. Plugging loopholes of these rules is the essential factor required to accomplish the task more efficiently. Although compliance with the basic rules is an important issue, global evidence has demonstrated that compliance is imperfect. An important Japanese response to the emergence of this disease was the establishment of independent scientific committees to formulate strategies for adopting relevant disease and control countermeasures. These were the Food Safety Commission (FSC) of the Japanese Government Cabinet Office, and the Prion Expert Committee in the FSC to persistently provide independent advice on said strategies. In addition, the Expert Committee on the Impact of Cattle-Testing assessed the risk of human exposure to BSE agents in Japan. The screening test employed for detection of the expected fraction of BSE-infected cattle destined for slaughter yielded 20%, even if all slaughtered cattle were tested by the ELISA and Western blot. Provided that the removal of specific risk-materials was conducted properly, the discrepancy in changing the age limit to over 20 months of age was negligible for testing beef safety. Scrapie in sheep has been documented in the 18th century in the United Kingdom. Through studies of brain-to-brain transmission in the same species in 1935, Cuille et al. successfully isolated the culprit protein from the sheep brain. To transmit said protein from one animal to another, intracerebral inoculation was much more efficient than the intraperitoneal or oral route in certain species; i.e. the hamster and mouse. Since discovery of the more efficacious infection route, studies and development of prion research have undergone 4 developmental phases. Phase I depicted discoveries of the pathological features of Creutzfeldt-Jakob disease (CJD) and scrapie with typical lesions of spongiform encephalopathy, while Phase II revealed individual-to-individual (or cross-species) transmissions of CJD, kuru and scrapie in animals. Phases I and II suggested the possible participation of a slow virus in the infection process. In Phase III, Prusiner et al. proposed the 'prion' theory in 1982, followed by the milestone development of the transgenic or gene-targeted mouse in prion research in Phase IV. By strain-typing of prions, CJD has been classified as type 2 or 4 by Parchi et al. and Wadsworth as type-2 or -4 and type-1 or -2, respectively. Wadsworth type I is detected in the cerebellum, while Wadsworth type 2 was detected in the prefrontal cortex of 10% of sporadic CJD patients. In 1999, Puoti et al. reported the co-existence of two types of PrPres in the same patient. These reports indicated that PrPres-typing is a quantitative rather than a qualitative process, and the relationship between the molecular type and the prion strain is rather complex. In fact, previous findings of Truchot have correlated type-1 distribution with synaptic deposits, and type-2 with the arrangement of diffuse deposits in neurons. Although the normal function of PrPC has not been fully understood, recent studies have shown that PrPC plays a role in copper metabolism, signal transduction, neuroprotection and cell maturation. Further search for PrPC-interacting molecles and detailed studies using Prnp(-/-) mice and various type of Prnp(-/-) cell lines under various conditions are the prerequisites in elucidating PrP functions. In the pathogenesis of prion diseases, present results support the hypothesis that 'loss-of-function' of PrPC decreases resistance to oxidative stress, and 'gain-of-function' of PrPSc increases oxidative stress. The mechanisms of (i) the 'loss-of-function' of PrPC in enhanced susceptibility to oxidative stress and (ii) the 'gain-of-function' of PrPSc in generation of oxidative stress remain to be elucidated, although their mechanisms of action, at least in part, involve the decrease and increase in SOD activity, respectively.