Swirl

I have always been intrigued by Disease and its Molecular underpinnings. Thanks to an explosion of technologies and branches of study we now know much more about disease and our response to them than we probably did a few centuries ago. The beauty, however, is that the more we unravel, the more twisted the problem seems to get. Just as we feel that we have begun to grasp the single unifying concept of an infectious agent, then along comes a startling new discovery and turns all our careful theories on their heads!!!

I have been longing to write on the current topic for a while now, and finally today I decided to take the plunge. So here goes, Prion Diseases. I am sure everyone has at least heard of prion diseases. Ok if not Prion, then at least the phrase “Mad Cow Disease” should definitely ring a bell. The unique aspect of this disease is very evident when one examines the extremely lucid definition of a prion given by the website MedicneNet.com, “A disease-causing agent that is neither bacterial nor fungal nor viral and contains no genetic material. A prion is a protein that occurs normally in a harmless form. By folding into an aberrant shape, the normal prion turns into a rogue agent. It then co-opts other normal prions to become rogue prions”.

The Deadly Prion.. The Rogue Protein

The Deadly Prion.. The Rogue Protein

So in short, it is like a soldier who has turned against his country. A completely normal protein performing a perfectly useful function in a healthy body turns into a rogue agent causing severe, debilitating and often fatal diseases. Prion diseases are progressive disorders that affect the nervous system in both humans and animals. Symptoms include memory loss, dementia, and loss of motor control and personality changes that simply keep getting worse with time. Some of the well-known diseases in this class include the Creutzfeldt – Jakob disease (CJD), Fatal Insomnia (FI), and the Gerstmann-Sträussler-Scheinker syndrome (GSS). These diseases are very rare and only a small percentage of these are genetically inherited, most cases are random. One particular disease, namely the variant Creutzfeldt-Jakob disease or the vCJD can be caused by consuming contaminated beef, hence the appellation “mad cow disease”. Another more gruesome example is that of the Kuru disease observed for the first time in the South Fore tribe in Papua New Guinea. These tribes would acquire the infection after consuming contaminated human tissues as a part of post death cannibalistic rituals.

Nobel Laureate, Credited with Elucidating the Molecular basis of Prion Diseases

Dr Stanley Prusiner, Nobel Laureate

The central dogma that is now accepted by the research community with respect to Prion diseases was elucidated by Dr. Stanley Pruisner and it won him the Nobel Prize in the year 1998. In the case of inherited diseases the gene responsible is known as the PRNP gene or the prion protein gene. The inheritance is autosomal dominant, meaning just one copy of the defective gene is enough to cause the disease. Normally the prion protein is responsible for uptake of copper in the cells, for communication between neurons and for protection of the cells. Mutations in the PRNP gene cause cells to produce an abnormal form of the prion protein known as PrPSc. Iatrogenic or acquired cases can arise due to exposure to this abnormal protein.

PrPSc has the ability to convert the normal prion protein, PrPC, into more PrPSc. Build-up of this abnormal protein in the brain results in formation of clumps that destroy neurons, leading to the formation of microscopic holes in the brain, giving it the appearance of a sponge leading to the name “Spongiform encephalitis” The normal functional protein has a structure composed primarily of Alpha Helices whereas the Rogue protein has a Beta sheet rich structure.

Normal Prion with Alpha Helices and the Abnormal Prion rich in Beta Sheets

Normal Prion with Alpha Helices and the Abnormal Prion rich in Beta Sheets

It is now known that a number of neural disorders are caused due to the buildup of masses of abnormal proteins in the brain. Further, it is now evident that prion diseases can be transmitted via blood transfusions, this phenomenon having been first observed in sheep.

So is there any cure for this malicious disorder? Currently a number of compound are being used to ameliorate symptoms of Prion diseases. Many of these however, are highly toxic or not optimally effective and so most prion diseases are fatal and essentially incurable. Some of the common compounds that I came across are, Congo red and its analogs, anthracyclines, amphotericin B and its analogs, sulfated polyanions, and tetrapyrroles. Many of these are said to be able to delay propagation of the prions within the host. However, they may have toxigenic effects. Acridine and phenothiazine derivatives (eg, quinacrine, chlorpromazine) can inhibit the conversion of PrPC to PrPSc. However, animal trials hae not yet supported their use. For an excellent detailed article on Medication please refer to this link.

THE GOOD NEWS!!!!

According to recent research carried out by scientists at the MRC (Medical research Council), the indigenous tribal population of Papua New Guinea has developed resistance to the fatal prion disease, Kuru. The MRC is a center for excellence in Prion Diseases. Scientists studied around 3000 people from the Eastern Highlands including 709 who had participated in cannibalistic mortuary feasts, 152 of whom subsequently died of kuru. They discovered a novel and unique variation in the prion protein gene called G127V in people from the Purosa valley. The beauty is that this variation seems to confer almost complete protection from the dreaded Kuru disease, and hence, over a period of time this mutation has been “selected” by evolution. This variant gene has not been found anywhere else in the world.

Lead author Professor John Collinge, Director of the MRC Prion Unit said:

Dr. John Collinge- Lead Researcher, MRC

Dr. John Collinge- Lead Researcher, MRC

“It’s absolutely fascinating to see Darwinian principles at work here. This community of people has developed their own biologically unique response to a truly terrible epidemic. The fact that this genetic evolution has happened in a matter of decades is remarkable. Kuru comes from the same disease family as CJD so the discovery of this powerful resistance factor opens up new areas for research taking us closer to understanding, treating and hopefully preventing a range of prion diseases.

The Results of this research are likely to take us a step forward in understanding the strange workings of prion diseases and, in time, I am sure we will have within our arsenal a cure foe these dreadful and fatal diseases. Kudos to the scientists !!!