This is very informative!

GRAND ROUNDS PRESENTATION

Pathology's Dr. Nitya Ghatak Presents
Prion Diseases

Nitya Ghatak, MD, Professor of Neuropathology at Virginia Commonwealth University presented Prion Diseases: From Scrapie to Mad Cow, February 20 at the Pathology Grand Rounds.

"Without question," Dr. Ghatak began, "prion theory is one of the most revolutionary ideas in the study of infectious diseases. It captures the imagination. How can a protein, a substance that has no RNA nor DNA, infect individuals between and across the species barrier by itself?" Some scientists, he added, don't believe it can. They are interested in prions as markers of an infectious agent, possibly a slow virus, that has yet to be identified.

"I'd like to walk you through the history behind prion disease theory," he said. Then I'll bring you up-to-date, sharing the current thinking about prions today."

The major characters in this history, he explained, are goats, sheep, mankind and cows. The goats, the sheep and mankind all got sick. In 1959 it was discovered their stories overlapped when a research veterinarian, Dr. William Hadlow, made the observation that their brain changes were similar.

The goats and sheep had scrapie, a well known neurological disease described by Europeans in the 1750s. The sick animals showed behavioral changes, then progressively worsening ataxia (tremors), general neurological degeneration and death.

The people had two rare diseases with similar symptoms. One described in the 1920s--by German physicians Hans Gerhard Creutzfeldt and Alfons Jakob--was aptly named Creutzfeldt-Jakob disease (CJD). The second, described in the 1950s, was called "Kuru," meaning "to tremble."

Creutzfeldt-Jakob had a wide range of manifestations. Dr. Ghatak pointed out, "The same disease was called by different names, depending on the form that was present." CJD was rare. Chances of getting it were described as one in a million. It was sporadic and uniformly fatal, usually within weeks or months. Most of its victims were older than fifty years of age. No one had any idea of its cause.

CJD victims showed behavioral changes, rapidly developing dementia, ataxia, blindness, coma, then death. During autopsy neurologists found major changes in the victim's brains. They were spongiform. "Literally, full of little holes," said Dr. Ghatak. There was a loss of neurons and reactive astrocytes were present. But, no inflammation, as one might expect from an infectious agent. Varying neurologic signs and symptoms were present depending on which part of the brain was involved.

Then they found Kuru, he continued, an exotic disease of only one people in the world--the Fore people of Papua, New Guinea. Its victims were the women and children who ritualistically consumed human brain in a funereal practice honoring the dead. Its symptoms were behavioral changes, ataxia, progressive neurological degeneration and death within a year.

Dr. Vincent Zigas a medical officer in New Guinea and Dr. D. Carleton Gajdusek a pediatrician and virologist who later won the Nobel Prize for his work, were the first to study this disease called "the laughing death" after one of its symptoms. In 1959, Dr. Igor Klatzo of the National Institutes of Health explained the neuropathology of Kuru and added an observation not yet documented, the presence of amyloid in the form of congophilic plaques in the brains of Kuru victims.

The collective of these different diseases gave rise to the concept of transmissible spongiform encephalitis or TSE. Interestingly, in the 1960s, since the subject of transmissibility was very popular among researchers and clinicians at the time, Dr. Ghatak and his colleagues at the Albert Einstein College of Medicine, Bronx, NY, sent tissue from two CJD cases they had to Dr. Gajdusek. They never heard back, Dr. Ghatak said.

It was in 1982 that Dr. Stanley Prusiner, Professor of Neurology, Virology, and Biochemistry at the University of California San Francisco developed Prion Theory for which he later won the Nobel Prize. He isolated what he believed to be the transmissible agent from hamster brains infected with scrapie--a misfolded protein particle. He named it PRION for proteinaceous infectious particles.

According to the theory, the prion protein, PRNP, found normally in animals in the form of PrPc, becomes conformationally modified into its isoform PrPsc, considered "infectious." The conformational changes make it resistant to enzyme digestion. Its "infectious" character arises when one prion acts as a template for the creation of more prions presumably with the help of a pathological chaperone. These prions aggregate and form amyloid giving rise to the typical symptoms.

Finally, as the history goes--the cows enter the picture. They became major players when another form of TSE, bovine spongiform encephalitis (BSE), commonly called "mad cow disease," showed up in the United Kingdom in 1985. The cows had been given high-protein feed made from the ground-up carcasses of sheep. Like other TSEs, BSE caused a change in temperament, abnormal posture, lack of coordination, difficulty in rising and finally death for the cows.

The tragedy is that BSE crossed the species barrier into humans causing, "A peculiar kind of CJD named variant CJD (vCJD)," said Dr. Ghatak. Its victims were atypically young. In fact, the connection was first made in a 19 year old man diagnosed with it. It sparked a wave of fear that led to the slaughter of 4.5m cattle in the UK and across Europe. A total of 153 people had died by 2003. All but 10 of the victims were from the UK.

The symptoms of vCJD are familiar part of the story by now. It first presents as a psychiatric problem, explained Dr. Ghatak, with dementia, anxiety, and depression. Then symptoms of progressive neurodegeneration appear including ataxia, coma and death within one year of onset. The incubation period can be long--as long as 20 to 30years. Pathologically, PrPsc accumulation is found in lymphoid tissue including the tonsils. The brain is spongiform and shows neuronal loss and amyloid plagues.

Phenotypes of CJD are modified by 2 factors, the genotype of PRNP polymorphic codon 129, and the type of PrPsc, either Type 1 and Type 2. So far, all tested cases of vCJD have been homozygous for methionine.

Today, CJDs are generally classified as familial, sporadic, iatrogenic, or variant. Familial, or inherited, forms include fatal familial insomnia (FFI) and Gertsman-Straussler-Scheinker (GSS) Syndrome. At least twenty different mutations are known. Sporadic CJD (sCJD) accounts for 90% of the cases. In the recent past, iatrogenic CJD arose in patients who had received tissue grafts, particularly cornea and dura, and human growth hormone.

The mystery remains, said Dr. Ghatak, but evidence is building that TSE's are not caused by prions acting alone. "There's something," he said, "about the conversion process from PrPc to PrPsc at the cell membrane...

For more information about his work, you may contact Dr. Ghatak at nrghatak@vcu.edu.
Source: http://www.pathology.vcu.edu/news/grand51.html