Kuru disease caused by Prions

I am here with another post which may interest biology and medical students more. Again, the post is inspired by my dear dad. It is a pleasure talking to him!! He has discussed this topic at length in his book - Molecular Biology published in 2008.
Back to the topic, the interesting part for non-biology readers is that it reflects on a very peculiar kind of disease caused by no bacteria or virus but some other particle called Prion. Another interesting fact is how it infected many in a small island of New Guinea near Australia.

Prion


Prion is Proteinaceous infectious particle.

What is Kuru disease

Kuru disease is caused by prions (Proteinaceous infectious particle) discovered by Carleton Gajdusek in 1957 in New Guinea, an island near Australia. Kuru is a local tribal word which means "shaking or shivering". It was found that the victims were primarily women and children.

In the initial stages the victims exhibited involuntary tremors. This was followed through stages of increasing debilitation, dementia, and paralysis which ultimately claimed their lives.

The cause found

Upon hearing the symptoms of the disease, Gajdusek had concluded that the people of this region were probably suffering from an epidemic a viral encephalitis. Encephalitis means inflammation of the brain cells. The disease was probably being spread through the population by the ritual practice of eating parts of the bodies of relatives who had died. Since it were the women in the villages who prepared the bodies and were likely to engage in this form of cannibalism, they were found to be the ones who were at the greatest risk of infection, which got passed on to the children.

Over the ensuing months, Gajdusek helped with the care for the sick villagers in a makeshift hospital, performed autopsies on those who died, and prepared tissue and fluid samples that were sent to laboratories in Australia. In one of the many letters to the outside world, Gajdusek wrote

we had a kuru death and a complete autopsy. I did it at 2 AM during a howling storm in a native hut, by lantern light and I sectioned the brain without a brain knife. The sections revealed that victims of kuru were dying as the result of widespread degeneration of their brains.

The evidence began to mount that kuru is not a viral infection. Patients dying from kuru showed none of the symptoms that normally accompany central nervous system infections, such as, fevers, inflammation of the brain, and changes in the composition of cerebrospinal fluid. In addition, the best virology labs in Australia were unable to culture an infectious agent from the diseased tissue samples. Gajdusek began to consider alternate explanations for the cause of kuru. It was possible that the affected villagers were being exposed to some type of toxic substance in their diet. Blood analysis were performed in the hopes of finding elevated levels of trace metals or other common toxins, but no chemical abnormalities were found.

At one point, Gajdusek thought that kuru might be an inherited disease but he concluded from discussions with geneticisits that this was very unlikely. For example it would be practically impossible for an inherited disease:
a) to be of such high lethality and apparently of recent origin to attain such a high frequency in a population
b) to manifest itself in individuals of such diverse age-groups from young children through older adults.
c) to strike an equal number of young boys and girls but strike 13 times as many as adult women as men.
d) lastly to appear in a person in another area of the island who had moved into the affected population.

There seemed to be no reasonable explanation for the cause of kuru.

Connection between Scrapie and Kuru

Elsewhere, William Hadlow, an American veterinary pathologist, was working on a degenerative neurologic disease called Scrapie that was common in sheep and goats. In 1959, Hadlow visited an exhibition in London sponsored by a British pharmaceutical company where he saw a display of neuropathologic specimens prepared by Gajdusek. The specimens were from a person who had died of kuru. Hadlow was struck by the remarkable resemblance between abnormalities in the brains of kuru victims to those in the brains of sheep that had died from Scrapie.

Scrapie was known to be caused by an infectious agent. This had been demonstrated by transmitting the disease to healthy sheep by injecting them with extracts prepared from sick animals. Because the agent responsible for Scrapie was able to pass through filters that retarded the passage of bacteria, it was presumed to be a virus. Unlike other viral diseases, however, symptoms of Scrapie did not appear after an animal was infected with the pathogen and therefore, became known as "slow virus". Hadlow concluded that Kuru and scrapie were caused by the same type of infectious agent and published his speculation in a letter to the British Medical journal, Lancet. This acted as a catalyst and after several years of work, Gajdusek was finally able to demonstrate that Kuru can be transmitted from extracts of human tissue to laboratory primates. The incubation period between the inoculation of the animals and the appearance of symptoms of the disease was nearly two years. Kuru became the first human disease to be caused by a slow virus.

Final link - The CJD

Several years earlier, Igor Klatzo, a neuropathologist at the National Institute of Health (NIH), had told Gajdusek that a rare inherited condition called Creutzfeldt-Jacob disease (CJD) produced brain abnormalities that resembled those of Kuru. Gajdusek and his co-workers demonstrated using extracts prepared from the biopsy of the brain of a person dying from CJD, that CJD could be transmitted to animals.

Discovery of Prion

How can an inherited disease such as CJD be linked to the presence of an infectious agent?
The answer to this question was revealed in the next 15 years largely through the work of Stanley Prusiner and his colleagues at the University of California, San Fransisco. They came to the conclusion that the agent was very small, much smaller than any known virus. Second, the agent appeared to lack a nucleic acid component and to be composed exclusively of a protein.

The second conclusion was based on exhaustive treatment of infectious brain extracts with enzymes or other substances that would digest or destroy either proteins or nucleic acids. Protein destroying agents such as proteolytic enzymes like phenol, rendered extracts harmless whereas, nucleic acid destroying treatments, including various types of nucleases and UV radiations had no effect on infectivity. Prusiner named the agent responsible for Scrapie and presumably for Kuru and CJD as well, a prion which stood for a proteinaceous infectious particle.

In 1985, it was shown by Prusiner and his co-workers that the prion protein is encoded by a gene within the cells' own chromosomes. This gene is expressed within a normal brain tissue and encodes a protein of 254 amino acids designated PrPC (Prion protein cellular) whose function remains unknown.

Unanswered questions

The idea that an infectious disease can be caused by an agent consisting solely of a single protein remains controversial. Some biologists believed that the prion protein is associated with a small piece of nucleic acid that is yet to be discovered.

Another matter that remains unanswered is the mechanism by which the infectious agent is able to replicate within an infected individual. Replication is generally attributed only to nucleic acids. How is it possible for a protein to produce more of itself?

While prion diseases are very rare, other degenerative neural diseases such as Alzheimer's and Parkinson's disease are very common. It is hoped that the study of prion disease will prove useful in understanding the basis of the more familiar human conditions.

Any reader who can throw more light on this is more than welcome to solve this mystery of prion. I wish the mystery of this new organism does interest many! :)