Reviewing the big P...Prions!

Student guest post by Rajeshwari Nair

Discussion on consumption of meat products is a common occurrence in my household. Hailing from India, I have always relished meat dishes that my mom cooks up, hot and spicy! However, there is always a nagging guilt on eating animals. People have tried convincing me that we are all part of the food-chain in this ecosystem, so either eat or be eaten. However, in recent times one thought crosses my mind when I stuff that yummy piece of meat in my salivating mouth, will this karma get to me soon? Will my brain dissolve as I chew on the brain of this mute four-legged creature? All this began not very long after my first lecture on 'Prion diseases'. I sit in class thinking, 'Hey we are built of protein matter, we eat forms of protein daily, we digest proteins daily and look at what a tiny solitary protein can do to us.'

Prions (pronounced pree-ons) are an acronym for proteinacious infectious particles. A normal prion protein, designated as PrPc is produced by every cell in a human body. This protein is encrypted by a highly conserved gene PrP in the human genome (chromosome 20) [5]. Okay all this sounds just fine, so what about this protein? Well believe it or not, it has a life of its own. Yes, superior to viruses and bacteria and it does not need a DNA or RNA to survive or infect other living forms.
Prion protein has a beautiful structure made of alpha helix sheets. This protein can be digested by enzymes generally used to breakdown proteins. However, something goes awry and this awe-inspiring protein changes to a structure with several beta sheets. What transpires here is really not well understood. However, there have been several hypotheses, what we know better as educated guess! The protein gets misfolded (PrPsc) and leads to further misfolding of normal PrPc. Thus there is a school of thought that the 'first misfolded prion protein' may be the infectious agent [1]. However, propagation process does not stop at this. These misfolded proteins form plaques and thus begins the destruction of a thinking organ, the brain. Hey, but why did the first prion protein misfold. It could be due to something you inherited from your parents, something you ate at your favorite food joint, a mutation or just like that...research is ongoing!

Abnormal prion proteins cause a spectrum of diseases known as transmissible spongiform encephalopathy or TSE. Prion diseases are progressive, neurodegenerative disorders that affect animals as well as humans. The disease spectrum includes gory sounding conditions in humans such as true Cruetzfeld-Jakob Disease (CJD), Kuru (spread by ritualistic cannibalism), Fatal Familial Insomnia, and Gerstmann-Sträussler-Scheinker syndrome [4]. Remember the 'Mad Cow disease' which caused chaos in England way back in 1986. Farmers back then fed their cattle soybean. However soybean did not grow well, so these farmers found an alternative. They fed their cattle animal byproducts, brain, blood, bones from other cattle and sheep. Hmm...I am thinking 'animal cannibalism'. Anyways, these infected cows found their way to markets in England, either as fuel (food) or fertilizer (manure). People who came in contact with these infected animals soon took ill, and contracted what is known as Variant form of CJD (vCJD). At least 157 people were infected and killed till 2004. United States has not been oblivious to this disease. Holman et al., reported an analysis of death certificates of US residents which estimated 6,917 deaths with CJD, 1979-2006. Most of these deaths were among people 65 years and older and mostly whites. At least three patients have died of vCJD since 2004 [2]. Occurrence of prion diseases could be familial (inheritance of mutated prion genes), just out of the blue with no known cause (sporadic), ingestion of infected material, and even through transplant of infected organs such as the brain, ocular tissue or human pituitary growth hormone [4]. Signs and symptoms depend on part of the brain infected and age at infection. Disease symptoms can be easily mistaken for other neurological conditions such as Alzheimer's, Parkinson's or even just depression. Prions can turn our brain into a complete mush which may not be diagnosed until an autopsy is performed. Something to ponder about may be...increase in mental health conditions such as Alzheimer's, dementia and others. Ever speculate there may be a prion disease since above mentioned conditions are often clinically diagnosed.

It is time to further investigate this situation and fill in existing gaps in knowledge. Various forms of therapy are under investigation with focus on preventing structural changes to the normal prion, thus preventing disease. Drugs which can cross the blood brain barrier are being considered to combat prions. Some antimalarial drugs such as Mepacrine, an anti-tumoral drug Iododoxorubicin and even Tetracycline are being considered potential for anti-prion therapy. Some of these drugs have been tested on animal models and cell cultures, and have shown robust effects. Even a vaccine was being tested by clinical trial as a method to slow disease progression [3].

Even though all these facts sound alarming, one may be lead to think why should we care. There are hardly any cases occurring, there are several other battle to be fought. This one can be laid to rest for now. On the contrary, in today's world with new emerging and re-emerging diseases prions could be a significant assault on living forms. Also, globalization and environmental interactions could act as fuel to this fire. We hear of diseases being transmitted from animals to human (zoonotic) and the reverse. Is there a chance that prion diseases could add to this list?

References:

1.Gains MJ, LeBlanc AC. (2007). Canadian Association of Neurosciences Review: Prion protein and prion diseases: The good and the bad. The Canadian Journal of Neurological Sciences, 34: 126-145.

2.Holman RC, Belay ED, Christensen KY, Maddox RA, Minino AM, Folkema AM, et al. Human prion diseases in the United States. PLoS ONE. 5;1:e8521.

3.Caramelli M, Ru G, Acutis P, Forloni G. Prion Diseases Current understanding of epidemiology and pathogenesis and therapeutic advances. CNS Drugs. 20;1:15-28.
4.Pedersen NS, Smith E. Prion diseases: Epidemiology in man. Acta Pathologica, Microbiologica et Immunologica Scandinavica. 110:14-22.

5.Glatzel M, Stoeck K, Seeger H, Lührs T, Aguzzi A. Human prion diseases:molecular and clinical aspects. Archives of Neurology. 2005;62:545-52.