3 minute read


Prion Diseases

Historically, prion diseases have been given distinct names. Scrapie is a naturally occurring prion disease of sheep and goats that was first documented in Iceland during the eighteenth century. BSE or mad cow disease is a prion disease of cattle and is believed to be acquired through scrapie-contaminated foodstuffs. Kuru, a prion disease found among the Fore tribe of New Guinea, was shown by D. Carleton Gajdusek to be transmitted by the consumption of human tissue, particularly brain tissue, during funerary rituals. Gajdusek was awarded the 1976 Nobel Prize in physiology or medicine for this contribution. The early symptom of Kuru is a loss of coordination, followed by mental confusion and, ultimately, death. It has virtually disappeared since 1958, when the practice of eating human tissue was more or less eradicated in New Guinea.

CJD is the most common human prion disease, affecting about one in a million people. The main symptom is dementia, along with other neurological signs. There are three forms of CJD. Sporadic CJD, the cause of which has yet to be found, is a spontaneous disease that accounts for a majority of CJD cases. Familial CJD affects people who carry a mutation in the PrP gene on chromosome 20. The third form, called iatrogenic CJD, is the result of accidental transmission during medical treatments. A newly emerged CJD phenotype, commonly called variant CJD, has occurred in the United Kingdom since 1985. Variant CJD has a unique disease profile, and may result from the consumption of BSE-contaminated meat products. It has been diagnosed mostly in young people who initially seek treatment for psychiatric symptoms. Gertsmann-Sträussler-Scheinker (GSS) syndrome A schematic model for the action of prions, showing how the "bad" prion alters the shape of the "good" prion. is a familial prion disease resulting from a mutation in the PrP gene. The main symptom of GSS is the loss of coordination and dementia. Fatal familial insomnia (FFI) is another a familial prion disease in which fatal dementia follows the loss of physiological sleep.

Although human prion diseases manifest as three etiologically different forms—spontaneously (sporadic CJD), through inheritance (familial CJD, GSS, and FFI), and by infection (iatrogenic CJD, kuru, and possibly the new variant CJD), they nonetheless share a common pathogenetic event. Within the framework of "protein only" hypothesis, they all involve the protein conformational change that converts PrPC to pathogenic PrPSc. Such a structural change in PrP may be triggered by a rare spontaneous event leading to a sporadic disease, a mutation that causes a familial disease, or exposure to foreign PrPSc, leading to an acquired disease. The "protein only" hypothesis provides a plausible mechanism underlying the pathogenesis of all forms of prion diseases. Moreover, it also helps explain the tremendous variability in prion-associated disease phenotypes. Structurally distinct variants of PrPSc may accumulate in different regions of the brain and initiate pathogenic changes that may eventually lead to distinct pathology in different areas of the brain, and subsequently the particular disease symptoms.

The concept of the prion and the role of protein conformation in disease pathogenesis have renewed inquiry into the causes of other and more common neurodegenerative disorders, such as Alzheimer's disease, Hunt-ington's disease, and Parkinson's disease. A common hallmark of all these diseases, as in prion diseases, is the conversion of an otherwise soluble and functional neuronal protein into a β-sheet rich and protease-resistant protein that has a higher tendency to aggregate and is harmful to the brain. These common pathogenetic features raise the hope that therapeutic interventions based on the same principles may be effective in all these diseases.


Pierluigi Gambetti

and Shu G. Chen


Cohen, F. E., and S. B. Prusiner. "Pathologic Conformations of Prion Proteins."Annual Review in Biochemistry 67 (1998): 793-819.

Prusiner, S. B. "Molecular Biology of Prion Diseases." Science 252 (1991): 1515-1522.

———. "The Prion Diseases." Scientific American (1995): 48-57.

———. Prion Biology and Diseases. New York: Cold Spring Harbor Laboratory Press,1999.

Additional topics

Medicine EncyclopediaGenetics in Medicine - Part 3Prion - A New Infectious Agent, Role Of Protein Conformation, Prion Diseases