The Mutagen Hypothesis

In 1997, Stanley Prusiner was awarded the Nobel Prize for his prion hypothesis, which is still used today to describe the propagation of some of the deadliest diseases that affect the central nervous system. However, the prion hypothesis remains controversial, as it does not adequately describe the mechanism by which infection occurs, inheritance of diseases such as CJD, or variations among the infected proteins (i.e. “prions”). I propose a counter argument to the prion hypothesis, the “mutagen hypothesis,” to explain the uncertain aspects of pathogenesis of these diseases. This new hypothesis is supported by and explains findings from previous experiments performed by other scientists – findings that the prion hypothesis failed to explain. The Mutagen Hypothesis Since the 1960s, scientists have searched, without success, for the main cause of a group of similar diseases, which includes Creutzfeldt-Jacob Disease (CJD) among the general population, “kuru” among the Fore tribe of New Guinea, “scrapie” among sheep, and “mad cow disease.” In the 1980s, one scientist believed he had found the cause – a small proteinaceous infectious particle, which he called a “prion” (Prusiner 1991). The idea that a protein could serve as an infectious agent challenged the long-standing view that only nucleic acids could spread disease (JYI 2008). Although there is hardly any doubt that the infectious agent is not a nucleic acid, there are many reasons to suspect that a prion is not the main cause of transmissible spongiform encephalopathy (TSE), but may just be acting as a sort of “accomplice.” My hypothesis is that the real cause of TSE is a mutagen (an agent which can cause mutations in a person’s DNA) that attaches to prion proteins and causes them to misfold. Normal individuals possess a PrP gene that encodes a protein called PrP c . This protein has an unknown function, but it may be involved with the transport of copper ions, which are bound by the N-terminal end of the protein (Riesner 2003). According to the Prion Hypothesis, an abnormal form of the PrP c protein, called a “prion” and designated PrP sc (c = cellular, sc = scrapie), interacts with normal PrP c , forming more and more PrP sc in a chain reaction. Unlike PrP c , PrP sc is insoluble, cannot be destroyed by high temperatures, and is usually resistant to degradation by protease K (Riesner 2003). Experiments have shown that mice without a PrP gene are not susceptible to infection by PrP sc while those with the gene are (Prusiner 1991). No nucleic acid has been found associated with PrP sc , and it was therefore concluded that the protein must be the infectious agent (Prusiner 1991). However, the prion hypothesis does not attempt to explain how TSEs can be inherited. It assumes that vCJD, sporadic CJD, and familial CJD are all different diseases (Prusiner 1991). It is believed that familial CJD is caused by a mutation in the PrP gene, and that individuals who develop sporadic CJD might have also undergone mutations at various times (Prusiner 1991). However, it is possible that the variants of CJD are actually the same disease, and that PrP c and PrP sc are the same protein, produced by the host’s own cells. The discovery of a mutagen that can attach to the PrP c protein would explain how diseases such as scrapie, BSE, and CJD can be inherited – as the mutagen would not only react with the normal prion protein, but also cause mutations in the PrP gene (as shown in Fig. 1). A study has shown that heterocyclic mutagenic amines such as Trp-P-1, Trp-P-2, and Glu-P-1 can bind to proteins such as α-lactalbumin and βlactoglobulin found in cow milk (Yoshida et al. 1991). Mutagenic amines were isolated from cooked beef and fried hamburger, and were shown to cause mutations in mice and rats (Yoshida et al. 1991). In addition, the mutagenic amines would bind more readily at a higher temperature and lower pH. Interestingly, experiments in which PrP c was converted to the Figure 1. Green circles = PrP c , Red circle = protein attached to mutagenic amine, Green stars = misfolded PrP c .