Recent cases of Mad Cow Disease have focused the public attention on prion diseases and the small proteins that are believed to cause them. The scientific community has been slow to recognize this mechanism of disease, since prion-caused encephalopathies can demonstrate diverse symptoms, and share characteristics with other disorders, such as dementia.
Prions, as the acronym (Proteinaceous Infectious Particles) suggests, are small proteins that are typically expressed in brain tissue, and may exist in a normal or abnormal shape. The prion protein is encoded by a gene found on the human chromosome 20. Usually, the prion protein is translated in neural tissue, folds into its normal conformation, carries out its cellular role, and is eventually degraded by enzymes. The abnormal prion, however, folds differently from its normal counterpart. This different shape makes it more difficult to degrade, and leads to the brain damage that is seen in patients with prion diseases.
The discovery of prions is credited to Stanley Prusiner, a professor at the University of California, San Francisco, School of Medicine. Professor Prusiner coined the term 'prion' to describe an apparently new phenomenon of disease transmission and was awarded the Nobel Prize for Medicine in 1997. Prion disease, however, has been documented for centuries in various species. Scrapie, a disease that affects sheep and goats has been recognized since the 1700s. Similarly, bovine spongiform encephalopathy (BSE) is a progressive neurodegenerative disease that affects cows. Prusiner won the Nobel Prize for his 'prion hypothesis' that was originally published in 1982, although investigation into human prion diseases dates back decades earlier.
Carleton Gajdusek, an American pediatrician, was instrumental in laying the groundwork for Prusiner's 'prion hypothesis'. In the 1950s, Gajdusek studied a rare disease, kuru, that was infecting the Fore tribe of New Guinea highlanders. He found that the devastating neurodegeneration exhibited by certain members of the Fore tribe could be traced to ritual cannibalism. Autopsied brains of the victims showed a similar type of brain damage to the brains of sheep affected with scrapie. Gajdusek also studied patients with Creutzfeld-Jakob disease (CJD) and noted the brain tissue had a similar sponge-like appearance. Based on these apparently diverse diseases, Gajdusek postulated a new type of infectious agent was responsible. Although the term "prion" didn't come into use until the 1980s, Dr. Gajdusek was awarded the Nobel Prize for Medicine in 1976 for the work that linked these disparate afflictions.
The most common human prion disease is Creutzfeld-Jakob Disease, a progressive neurodegenerative disorder that can arise randomly ("sporadic CJD") or as a result of contamination with infected tissue. Because prions are proteins, and proteins are coded for by genes, some prion diseases can be inherited. A small percentage (10-15%) [http://www.albany.net/~tjc/prion.html]of CJD is attributable to an inherited gene mutation. A similar mutation is responsible for other, less common, prion diseases. A fatal form of insomnia caused by progressive prion brain damage (fatal familial insomnia - FFI) is caused by a mutation in the prion gene, as is Gertsman-Straussler-Scheinker disease (GSS), a similar affliction to CJD. An umbrella term that refers to the family of prion diseases is transmissible spongiform encephalopathies (TSE).
The infectious nature of the prion protein is based upon its conformation once it is translated and folded. Usually, the protein product of the prion gene folds into a structure that consists primarily of alpha-helix coils. This shape is known as PrPC (prion protein, cellular) and allows the protein to function normally. Although the role of the normally folded prion protein is not known, it is believed to play a role in synaptic message transmission in brain tissue. When the protein has fulfilled its purpose, it is degraded by brain tissue enzymes. The way in which a protein folds after being translated is critical to the protein's function. This alternate folding means that the same amino acid sequence can have devastating consequences if it folds in a different manner. In the case of the abnormal prion protein, this abnormal conformation consists of more beta-pleated sheets than alpha-helices. (This abnormal form is denoted PrPSc - prion protein, scrapie). The different shape of the infectious prion protein makes it resistant to degradation by enzymatic function. The protein builds up in brain tissue, damaging neurons and causing the sponge-like (spongiform) appearance that is typical of prion disease-infected brains.
Prion diseases progress because the abnormally folded proteins can 'infect' nearby, normal proteins, and cause them to refold into the abnormal conformation. In this way, a small amount of abnormal prions can convert other proteins and lead to a progressive neurodegeneration.
CJD, the most common prion disease was named for the German psychiatrist (Creutzfeldt) and neurologist (Jakob) who first identified it in 1920. The overall incidence of this prion disease is one in one million (Prusiner, 2003). Approximately 85% of CJD cases arise sporadically, possibly when a normal prion protein misfolds and infects surrounding tissue. The other cases of CJD occur as a result of an inherited mutation in the prion protein, or are acquired from contact with infected tissue. These acquired cases have been caused by transplants from affected cadavers (corneas, dura mater) as well as infection due to contaminated surgical instruments. About 100 cases of CJD were caused by a growth hormone treatment the victims received as children that was harvested from human cadavers.
TSE (transmissible spongiform encephalopathy) has a long period of dormancy (sometimes decades) before symptoms appear, often in middle age. The typical age of onset ranges from 45 years old to 75, although once symptoms appear the disease progresses rapidly. CJD victims usually die within six months of the appearance of symptoms (http://www.st-marys.nhs.uk/specialist/prion/factsheets/priondiseases.htm).
When Prusiner published his 'prion hypothesis' in 1982, much of the scientific community was skeptical. Few scientists initially believed that a protein could be infectious, since proteins lack their own DNA. In the past two decades, evidence has accumulated that supports prions as the cause of such diseases as CJD and GSS. Although prions lack their own genome, the differential folding of normal and abnormal prion proteins provides the mechanism for prion infection and transmission. The prion hypothesis has been supported by the fact that prion-infected tissue can go on to infect other tissue, the basis for the acquired form of CJD. Laboratory experiments with animals have demonstrated the infectious potential of extracted prion proteins. The prion hypothesis has further support against the argument that proteins can't prove infectious. Tissue samples from victims of CJD prove to be just as infectious when treated with UV radiation, which would mutate any causative DNA or RNA. Additionally, CJD victims have no typical symptoms of infection found in bacterial, parasitic or viral infections; that is, there is no inflammation, no fever and no evidence of antibody accumulation.
Skeptics of Prusiner's prion hypothesis believe a protein can't be the infectious agent because it lacks its own genetic material. This school of belief usually asserts that prions may be present in TSEs, but are not the causative agent. An as-yet undetected virus is thought to be the causes of spongiform encephalopathies. Some support for this theory may be inferred by the fact that the normal prion protein cannot be made infectious by in vitro manipulation. As yet, even altering the conformation of the prion protein to the apparent abnormal form does not render it infectious. Prion theory detractors point to this as evidence that a virus is more likely to be the infectious agent.
The elucidation of prion theory was a fairly recent development, despite the well-known cases of diseases such as kuru and CJD. This is due, in part, to the fact that the symptoms of prion disease are similar in most cases to dementia, as well as to the far-flung geography of acquired cases. Because prion disease is a progressive, degenerative brain disease, the tissue damage may cause personality changes and memory problems, followed by impaired motor control, and communication difficulty. In many cases of CJD, the symptoms are mistaken for dementias such as Alzheimer Disease or other neurodegenerative diseases such as Parkinson Disease or ALS. These similarities between CJD and other, more common diseases, is one challenge in diagnosing prion diseases.
When a patient presents with symptoms that indicate prion disease, a series of diagnostic tests may prove useful. Some of these tests are primarily useful in ruling out other causes of disease. Blood and urine tests, brain MRIs and testing the cerebrospinal fluid (CSF) can often rule out more common diseases, stroke or infection. Blood tests may also be used to test for the genetic mutation that causes hereditary prion disease. MRIs can be used to rule out strokes, as well, "in variant CJD a specific change on MRI is frequently observed in an area known as the thalamus." (http://www.st-marys.nhs.uk/specialist / prion / factsheets / diagnosingpd). In the past, brain biopsies were carried out to test for the presence of the abnormal prion protein. This is gradually being replaced by a tonsil biopsy, which has shown to be a site of PrPSc accumulation. An electroencephalogram (EEG)…