Slowly but Surely

            Few pathogens inspire fear to the degree that prions do. As the culprit behind such mysterious diseases as mad cow disease and Familial Fatal Insomnia, prions are avoided at all costs. In December of 2003 more than 30 countries closed their borders to all beef imports from the United States because just one cow from the state of Washington tested positive for mad cow disease (1). But what are prions? And why do they evoke such aggressive responses?

            Prions are not viruses but rather a misfolded form of a particular protein, called prion protein (PrP).  This protein, whose function remains unclear, is found throughout the body of healthy individuals in its properly folded state, known as PrP^C. When an individual is exposed to a prion, the misfolded form of PrP known as PrP^Sc, the prion can cause the normal protein to adopt its misfolded state. The normal PrP^C is converted into the abnormal PrP^Sc, which can then go on to convert more healthy proteins into their pathogenic form. Eventually amyloid plaques of these abnormal proteins build up, mostly in neuronal tissue, causing transmissible spongiform encephalopathies, holes in the brain that continue to grow until the individual has passed away.

            Prion diseases are universally fatal and there is no currently approved treatment to slow their advance (P). Because these diseases occur due to a single misfolded protein, they are not reliant on a nucleic acid based entity for transmission, as is every other known transmissible disease. It is for this reason that prions are not susceptible to normal sterilization procedures, including high temperatures and UV radiation. Transmission can occur solely due to ingestion of infected neural tissue or, as more recently suggested, via inhalation of air droplets (2). Because there is no known treatment for prion diseases countries tend to go to relatively extreme measures to prevent prions from crossing their borders.

            However, new research suggests that the use of PrP antibodies, both prophylactically and after infection has taken root, might help slow prion disease progression (3, 4, 5, 6).  These antibodies bind to specific regions of the normal PrP protein, helping them resist conversion to their prion form (4). However, these have mostly involved in vitro studies, which do not necessarily mean that there are practical clinical uses for anti-PrP antibodies in treating prion diseases. One of the main hurdles to overcome is getting these antibodies to target tissues in the central nervous system at concentrations high enough to have an effect. In order to do this the blood brain barrier (BBB), which is normally impermeable to antibodies, must be overcome. In the past this has meant inserting the drugs directly into the brain of mouse models. However, it would be more suitable in human patients for a less invasive delivery method to be used, especially considering the possible transmission of prions that could occur during brain surgery.

Prion Diseases: Are Researchers Finally Close to Uncovering a Cure?

Prion diseases are no laughing matter, although it might have seemed that way if you were a visitor on the island of Papua New Guinea in the 1950’s. It was here that members of the Fore tribe were suffering from what they had dubbed the “laughing sickness” due to the strange uncontrollable bursts of laughter that accompanied the debilitating shivering that struck it’s victims. The source of the disease, which came to be known as kuru, was found to be transmitted through ingestion of brain tissue during cannibalistic burial ceremonies. Ingestion of the diseased victims brain tissues exposed tribe members to a structurally altered form of the normally expressed cellular prion protein (PrP) which could react with healthy forms of the proteins in their brains, perpetuating further structural transformations.

There are a number of diseases spread in this manner, termed transmissible spongiform encephalopathies (TSE). All TSE's, which include the well-known mad cow disease (Creutzfeldt-Jakob disease), are inevitably fatal and lead to neurodegeneration, often mediated through pathologic neuroinflammation. The inflammation seems to be primarily due to the robust activation of microglial cells (Yang et al., 2008). Microglial cells are akin to the brain’s garbage trucks, constantly collecting cellular debris from the extracellular environment. This behavior coincidentally makes them especially fit for detecting the presence of extracellular pathogens as well.

Before a cure can be developed, researchers must first uncover the cellular mechanisms underlying the microglial-medated pathologic neuroinflammation observed in the victims of TSE. PrP106-126 is the region of the PrP protein that has been shown to mediate inflammatory and pathologic signaling following structural alteration. A recent study was able to use this peptide to identify many of the proteins and signaling molecules, thus potentially uncovering future targets for pharmaceutical therapies.