Prion Diseases

Prion diseases, also known as transmissible spongiform encephalopathies (TSEs), are a group of rare degenerative brain disorders characterized by tiny holes that give the brain a "spongy" appearance. These holes can be seen when brain tissue is viewed under a microscope. In some cases prion diseases are infectious. For example, variant Creutzfeldt-Jakob Disease (vCJD) was first spread to humans from cattle infected with BSE ("Mad Cow Disease"). Prion diseases are found in both humans and animals.

Cattle, such as the one pictured here, experience progressive degeneration of the nervous system if affected by BSE. Source: U.S. Dept. of Agriculture - Animal and Plant Health Inspection Service, APHIS /Dr. Art Davis

Other Names

• Inherited Human Transmissible Spongiform Encephalopathies
• Prion-associated disorders
• Prion-Induced Disorders
• Prion Protein Diseases
• Transmissible Dementias
• Transmissible Spongiform Encephalopathies
• TSEs

Types

Creutzfeldt-Jakob disease (CJD) is the most well-known of the human prion diseases. It is a rare type of dementia that affects about one in every 1 million people each year. Other human TSEs include kuru, fatal familial insomnia (FFI), and Gerstmann-Straussler-Scheinker disease (GSS). Kuru was identified in people of an isolated tribe in Papua New Guinea and has now almost disappeared. FFI and GSS are extremely rare hereditary diseases, found in just a few families around the world. A new type of CJD, called variant CJD (vCJD), was first described in 1996 and has been found in Great Britain and several other European countries. The initial symptoms of vCJD are different from those of classic CJD and the disorder typically occurs in younger patients. vCJD likely resulted from human consumption of beef from cattle with a prion disease called bovine spongiform encephalopathy (BSE), also known as "mad cow disease."

Other prion diseases found in animals include scrapie, which affects sheep and goats; chronic wasting disease, which affects elk and deer; and transmissible mink encephalopathy. In a few rare cases, prion diseases have occurred in other mammals such as zoo animals. These cases are probably caused by contaminated feed. CJD and other prion diseases also can be transmitted experimentally to mice and other animals in the laboratory.

Light photomicrograph of brain tissue showing the presence of typical amyloid plaques found in a case of variant Creutzfeldt-Jakob disease (vCJD). Magnified 158X. Source: CDC.

Signs and Symptoms

Symptoms of prion diseases vary, but they commonly include personality changes, psychiatric problems such as depression, lack of coordination, and/or an unsteady gait. Patients also may experience involuntary jerking movements called myoclonus, unusual sensations, insomnia, confusion, or memory problems. In the later stages of the disease, patients have severe mental impairment and lose the ability to move or speak.

Causes

Prion diseases are caused by an abnormal version of a protein called a prion (prion is short for proteinaceous infectious particle). Prion proteins occur in both a normal form, which is a harmless protein found in the body's cells, and in an infectious form, which causes disease. The harmless and infectious forms of the prion protein are nearly identical, but the infectious form takes on a different folded shape from the normal protein.^[1][2][3][4] Some scientists disagree with the prion hypothesis.^[5]

Human prion diseases can occur in three ways:

• Sporadic prion disease may develop because some of a person's normal prions spontaneously change into the infectious form of the protein and then alter the prions in other cells in a chain reaction.

• Inherited cases arise from a change, or mutation, in the prion protein gene that causes the prions to be shaped in an abnormal way. This genetic change may be transmitted to an individual's offspring.

• Infectious transmission occurs when prions from an infected person or animal are ingested and transmitted to a new case. These cases are relatively rare. Prion diseases cannot be transmitted through the air or through touching or most other forms of casual contact. However, they may be transmitted through contact with infected tissue, body fluids, or contaminated medical instruments. Normal sterilization procedures such as boiling or irradiating materials do not prevent transmission of prion diseases. Rarely, prion diseases can be transmitted by accidental exposure to prion-contaminated tissues during a medical procedure. This type of prion disease is called iatrogenic.

One type of prion disease in humans, variant Creutzfeldt-Jakob disease (vCJD), is acquired by eating beef products obtained from cattle with prion disease. In cows, this form of the disease is known as bovine spongiform encephalopathy (BSE) or, more commonly, "mad cow" disease. Another example of an acquired human prion disease is kuru, which was identified in the South Fore tribe in Papua New Guinea. The disorder was transmitted when tribe members ate the tissue of affected people during cannibalistic funeral rituals.

Familial forms of prion disease are caused by inherited mutations in the PRNP gene. This gene provides instructions for making a protein called prion protein (PrP). Normally, this protein is likely involved in transporting copper into cells. It may also play a role in protecting brain cells and helping them communicate. In familial cases of prion disease, mutations in the PRNP gene cause cells to produce an abnormal form of the prion protein known as PrP^Sc. In iatrogenic and acquired cases, an affected person develops prion disease from exposure to this abnormal protein.

In a process that is not fully understood, PrP^Sc has the ability to convert the normal prion protein, PrP^C, into more PrP^Sc. This abnormal protein builds up in the brain, forming clumps that damage or destroy nerve cells. The loss of these cells creates microscopic sponge-like holes in the brain, which leads to the signs and symptoms of prion disease.

Inherited prion disease

Genetic or familial forms of prion disease are caused by gene mutations inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person inherits the altered gene from one affected parent. In some people, familial forms of prion disease are caused by a new mutation in the PRNP gene. Although such people most likely do not have an affected parent, they can pass the genetic change to their children.

The sporadic, iatrogenic, and acquired forms of prion disease, including kuru and variant Creutzfeldt-Jakob disease, are not inherited.

Treatment

There is no treatment or cure for prion diseases. They tend to progress rapidly and usually culminate in death over the course of a few months to a few years. Treatment is aimed at alleviating symptoms and making the patient as comfortable as possible.

Research

The National Institute of Neurological Disorders and Stroke (NINDS) in the US conducts and supports research on prion diseases. This research is aimed at determining how abnormal prion proteins lead to disease, at finding better tests for diagnosing CJD and other disorders, and ultimately at finding ways to treat prion diseases.

Another US institute, National Institute of Allergy and Infectious Diseases (NIAID) has a laboratory in Hamilton, MT called the Rocky Mountain Laboratory (RML) where scientists also study prion diseases. Researchers at RML are examining how abnormal prion protein molecules cause TSE diseases. RML has had an active TSE research program since the 1960s. RML is one of the world's premiere laboratories for studying TSE diseases. Scientists there co-discovered and were among the first to clone the prion protein gene. NIAID scientists also discovered that abnormal prion protein can convert normal prion protein to the abnormal form. This may account for the disease process in the brain.

RML scientists have recently published findings from significant TSE studies. One study showed that when prion protein was modified to remove a membrane "anchor" in laboratory animals, scrapie infection caused formation of abnormal prion protein, but remarkably, did not result in disease. Researchers believe that without the membrane anchor, the abnormal prion protein is unable to damage the brain cells. These results suggest that drugs aimed at blocking interactions between normal and abnormal prion protein might be able to halt the progress of disease. In these same mice where the membrane anchor was removed, scrapie infection led to an accumulation of abnormal prion protein in heart tissue resulting in heart stiffness and malfunction. This research indicates that cardiac infection may be a new and previously overlooked feature of TSE diseases.

In another study, RML scientists used a new methodology to determine the size of the smallest infectious prions. These results demonstrate that the minimal size of the infectious material is equivalent to 5 to 10 prion protein molecules. It is possible, though not yet proven, that these smallest fractions are more infectious than the larger aggregates.

At Colorado State University in Fort Collins, NIAID has established an emerging diseases research center focused on studying CWD. This center is investigating the mechanics of CWD infection in deer and elk. Such studies underlie the search for improved diagnostics and therapies. The researchers also will seek to better understand the entire spectrum of disease transmission and under what circumstances CWD might "jump" to other species.

One recent study concluded that infectious prions are present in skeletal muscles of CWD-infected deer, demonstrating that humans consuming or handling meat from CWD-infected deer are at risk for prion exposure. Though there is no causal proof that CWD is capable of spreading to humans, researchers suggest that individuals use caution when handling infectious material or consuming any part of the animal that may be infected. More recently, the research group at Colorado State University has reported that infectious prions capable of transmitting CWD are found in the saliva and blood of affected deer. This helps to explain the ease of transmission of CWD among deer and suggests caution concerning contact with body fluids of infected animals.

Chronic wasting disease

The prion disease called chronic wasting disease (CWD), has been detected in U.S. deer and elk populations in 11 states. So far, scientists have uncovered no evidence that deer or elk with CWD might transmit some form of TSE disease to people who consume or have close contact with deer or elk.

More research is necessary to determine whether CWD poses any risk to humans, particularly because it is spreading over a wider geographical area in the United States. There have been several reported cases of CJD in individuals who have consumed venison, most much younger than the typical age associated with CJD. In each of these instances, careful investigations by CDC have shown no causal link between CJD and CWD in deer and elk populations. Continued surveillance is important, however, to assess any possible risk of CWD transmission to humans.

Cross-Species Transmission

At RML, studies are ongoing to understand the mechanisms by which TSE infections cross species. Experiments have demonstrated that species once thought to be resistant to certain TSE strains can be life-long carriers of the infection without ever becoming sick. RML scientists also are investigating whether CWD can be transmitted from deer or elk to other species after eating brain matter from deer or elk that are infected with CWD. That knowledge would provide valuable insight into whether this disease could possibly be transmitted to humans.

Therapeutic Approaches

Although there are no known ways to cure TSE diseases, scientists around the world are working to develop treatments. Using infected tissue culture cells for fast initial screening, NIAID researchers have tested thousands of compounds and identified hundreds of molecules that inhibit the formation of the abnormal form of prion protein. Further testing of the most potent of these inhibitors has revealed several that can prolong the lives of rodents if treatments begin soon after infection.

In collaboration with NIAID scientists and through a contract with NIAID, researchers at RML and at Utah State University in Logan are testing these compounds in animals. Other groups are further testing two of the inhibitors in CJD patients. New research at RML has shown increased survival times in mice given combination drug treatment therapy 14 to 28 days after scrapie inoculation. Although this will need further exploration, it is a positive step in treatment after the onset of clinical signs of TSE diseases.

RML researchers also have identified antibodies and short synthetic protein molecules (fragments of prion protein) that can block the conversion of normal prion protein to the abnormal form. If successful, these investigations will lead to safe and effective methods to prevent prion infections as well as therapies that work in either the pre-symptomatic or symptomatic phases of disease.

History

The idea of an infectious protein, or prion has always been controversial. Other infectious agents that catalyze their own reproduction, like bacteria and viruses, have their genetic information, or blueprint for reproduction, in nucleic acids (DNA or RNA). If the prion theory is correct, the information for reproduction in prions is located in the structure of the protein itself. The infectious prion causes normal cell proteins to misfold and become infectious prions.

Both the 1976 and 1997 Nobel Prizes for Medicine or Physiology were awarded for the discovery of prions. In 1976, Baruch S. Blumberg and D. Carleton Gajdusek were awarded "for their discoveries concerning new mechanisms for the origin and dissemination of infectious diseases."^[6] They studied kuru, a prion disease endemic in cannibals in Papua New Guinea. Gajdusek's career has been marred by a criminal conviction and admission that, in the course of his research trips in the South Pacific, Gajdusek brought children back to live with him in the United States and molested them.^[7][8]

In 1997, Stanley B. Prusiner was awarded the Nobel Prize "for his discovery of prions - a new biological principle of infection."^[9]

Mad Cows and Englishmen

In the 1980s "Mad Cow Disease" (bovine spongiform encephalopathy, BSE) appeared in Britain, directly killing almost 200,000 cattle, and causing another 5 million to be put down in the interests of public health.^[10]

Health officials in the United Kingdom have responded to evidence that beef infected with BSE may have spread vCJD to humans. Since the 1980s, when the BSE epidemic began in the United Kingdom, millions of cattle in Europe have been destroyed. In 1997, the U.S. Department of Agriculture (USDA) then reacted by outlawing feeding meat and bone meal products to cattle intended for U.S. consumption.

As of fall 2006, there have been 200 reported cases of vCJD worldwide, according to the Centers for Disease Control and Prevention (CDC). All of these cases were among people who ate beef in a country with a BSE outbreak, and nearly all (164 cases) were in the United Kingdom. Three U.S. cases have been reported, though these individuals were likely exposed to BSE agent while in the United Kingdom.

The first North American case of BSE was found in Canada in May 2003. Discovery of the first U.S. case of BSE followed in December 2003 in a Washington State cow. In June 2005, a second cow in the U.S. tested positive for BSE in Texas. USDA ascertained that the cow was born in 2001, 4 years after the 1997 USDA ban. A third BSE-infected cow was found in Alabama in March 2006. No cases of endemic vCJD have been associated with consumption of domestic beef in the United States.

Public Health

The major route of transmission of BSE to humans is likely to be consumption of BSE-infected beef. Meat products containing brain or central nervous system tissues (processed meats such as sausages, ground meat, meat pies, and pastries) are more likely to contain a high concentration of the infectious prion than other meat products and therefore represent a greater transmission risk.

Various predictions of the size of the vCJD epidemic in the United Kingdom range from a few hundred cases to more than one million.^[11]

The extreme resistance of prions to standard decontamination methods is a significant factor in the accidental transmission of prions; it has caused both the BSE epidemic and cases of iatrogenic CJD. Iatrogenic spread of variant CJD is an area of considerable concern for human health, particularly given the wide tissue distribution of prions from vCJD patients.

References

1. ↑ Lopez CD, Yost CS, Prusiner SB, Myers RM, Lingappa VR. Unusual topogenic sequence directs prion protein biogenesis. Science. 1990 Apr 13;248(4952):226-9. Abstract
2. ↑ Hsiao K, Baker HF, Crow TJ, Poulter M, Owen F, Terwilliger JD, Westaway D, Ott J, Prusiner SB. Linkage of a prion protein missense variant to Gerstmann-Sträussler syndrome. Nature. 1989 Mar 23;338(6213):342-5. Abstract
3. ↑ Owen F, Poulter M, Lofthouse R, Collinge J, Crow TJ, Risby D, Baker HF, Ridley RM, Hsiao K, Prusiner SB. Insertion in prion protein gene in familial Creutzfeldt-Jakob disease. Lancet. 1989 Jan 7;1(8628):51-2. Abstract
4. ↑ Pan KM, Baldwin M, Nguyen J, Gasset M, Serban A, Groth D, et al. Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins. Proc Natl Acad Sci USA. 1993 Dec 1;90(23):10962-6. Full Text
5. ↑ Manuelidis L, Yu ZX, Barquero N, Mullins B. Cells infected with scrapie and Creutzfeldt-Jakob disease agents produce intracellular 25-nm virus-like particles. Proceedings of the National Academy of Science 2007; 104: 1975-1970. Abstract
6. ↑ Nobel Foundation Web site.The Nobel Prize in Physiology or Medicine 1976.
7. ↑ News in Brief. Nature 385, 762 (27 Feb 1997).
8. ↑ Molotsky I. Nobel Scientist Pleads Guilty to Abusing Boy. NY Times. February 19, 1997.
9. ↑ Nobel Foundation Web site. The Nobel Prize in Physiology or Medicine 1997.
10. ↑ Watts JC, Balachandran A, Westaway D (2006) The Expanding Universe of Prion Diseases. PLoS Pathogens 2(3) e26 Abstract | Full Text
11. ↑ Trevitt, Clare R, Singh, Pramil N Variant Creutzfeldt-Jakob disease: pathology, epidemiology, and public health implications Am J Clin Nutr 2003 78: 651S-656. Abstract | Full Text

External Links

Public Library of Science: The Expanding Universe of Prion Diseases.

Creutzfeldt-Jakob Disease Foundation

Alzheimer's Association: This site includes information on CJD.

CJD Insight: Patient Support Site

National Organization for Rare Disorders

CJD Aware!: An information resource site for CJD.

[1]Alzheimer's Disease Education and Referral Center (ADEAR)]

National Hospice and Palliative Care Organization

PRNP gene information