Prion hypothesis

The idea that protein could be the solo infectious agent for prion disease was first proposed 43 years ago. Since then, the topic has been controversial. Although there is no evidence that proves such hypothesis yet, many evidences had indicated that the infectious agent is not nucleic acid based. On the other hand, there are also evidences that support the idea that the protein is at least not the solo component responsible for prion disease. There are still many outstanding questions waiting to be answered and thus the prion hypothesis still remains inconclusive.

What is Prion diseases?
Prion diseases, also previously referred to as subacute spongiform encephalopathies, slow virus diseases and transmissible dementias, are transmissible neurodegenerative conditions found in human and animals. The prion diseases found in animals are known as spongiform encephalopathy (BSE) and scrapie. Scrapie, commonly seen on sheep and goats, is one of the most well known prion diseases that has been recognized in Europe for over 200 years and is present in many countries today. The type of prion disease found in human can be classified into Creutzfeldt-Jakob Disease (CJD), Gerstmann-Straussler syndrome (GSS) and kuru. Such disease, however, is very rare in human, affecting approximately one person per million. Yet, researchers have put special focus on such disease due to the possibility that prion disease can be transferred to different species by dietary exposure to infected tissues. In fact, in 1986, an outbreak of a prion disease BSE in cattle of Great Britain drew more attention to such topic. It is likely that a majority of UK population have consumed the infected products. Such concern was confirmed when researchers discovered that Creutzfeldt-Jakob disease was linked to BSE. ,

In addition, around 70 years ago, scrapie was found to be transmissible between sheep and later passed on to nice. The causation of such transmission was most likely due to an accidental vaccine derived from an animal with scrapie. Researchers assume that virus was the infectious agents. However, certain evidence did not agree with such hypothesis. The hypothesis that the infectious agent was challenged as the result of the failure to directly identity such virus and the fact the infectious agent showed resistance to treatment expected in inactivate nucleic acid. Thus, prion hypothesis was proposed as an alternative explanation of how prion disease was transmitted. The prion hypothesis, also known as the protein only hypothesis, states that protein, rather than virus or bacteria, is the infectious agent of the prion disease. ,

What is protein hypothesis?
Protein hypothesis or prion hypothesis states that the misfolded prion protein, rather than virus or bacteria, is the infectious agent that result in the transmission of prion disease.

Evidences Support Prion Hypothesis
Even from the initial discoveries of the prion disease, it was clear that the infectious agent for prion diseases were different from conventional micro-organisms (such as virus and bacteria). Such observation was supported by the experiments of Alper. Alper subjected mouse brain affected by scrapie with ultraviolet light at multiple wavelengths, a condition which inactivates all nucleic acid to observe the effects on infectious agent of scrapie. The level of infectious agent, however, did not change. Such result indicates that the infectious agent is most likely not DNA or RNA based because even when UV radiation nears the peak of the absorption spectrum, there seems to have no effect on the agent. Alper believes that even with the most efficient repair system, a declination should still be detected if the infectious agent is nucleic acid based. However, the same studies also did not support the prion hypothesis. According to the study, if the infectious agent is protein based, a decline of infectious agent would appear when subjected to UV light at about 280mu. A declination was observed, however, it was not enough to create a statistical difference. In other words, the study remains inconclusive on whether the infectious agent is protein based. ,

Recent research seems to have a significant breakthrough in identifying the infectious agent. According to the article “identification of a protein that purifies with the scrapie prion”, a protease resistant prion protein (PrPsc) was found in the scrapie infected hamster brain which does not exist in healthy hamster brain. The molecular size of such protein was approximately 27,000 to 30,000 Daltons in sodium dodcyl sulfate polyacrylamide gel. Researchers were able to distinguish such protein from others due to its resistance to protease K. The initial result indicates the amount of this protein correlates with the tier of the infectious agent. , In fact, “immunoaffinity purification and neutralization of scrapie prion infectivity” by Gabizon R shows the infectivity remain constant throughout the purification of PrPsc. During the study, when PrPsc extracted from scrapie infected hamster brain was subjected to detergent lipid protein complex, which destroyed the structure of PrPsc protein, the scrapie infectivity decreases by a factor of 100. The direct correlation between the PrPsc and the infectivity indicates that PrPsc is most like involved in the infectious process. (18) Furthermore, researches show that the gene encoding PrP was the same in prion infected brain and healthy brain. Such result indicates the difference between PrPsc and PrPc (normal PrP protein) was due to post-translational activities (21). Another strong evidence that supports the prion hypothesis comes from the demonstration of PrnP-/-. Mice with such gene that lack both normal and mutated type of PrP proteins did not show signs of scrapie (29), which supports the hypothesis PrP protein must be present during prion disease. Furthermore, in 2001, Soto and his team successfully converted PrPc into PrPsc like structure with a very small amount of PrPsc in vitro. Such process is known as Protein Misfolding Cyclic Amplification (PMCA). PMCA allows prion to be produced in an accelerated rate and is widely used to study prion disease today. Such finding is also evidence of PrPsc triggering further misfolding and serving as a catalyst for prion replication (31).