What causes Creutzfeldt-Jakob disease?

If this hypothesis is proved true, it would represent one of the most radical new ideas in biology since the discovery of DNA. All infectious diseases, in fact all life, uses nucleic acids--DNA or RNA--to code the instructions needed for reproduction. Inactivation of the nucleic acids destroys the capacity to reproduce. However, when these same measures are applied to infected tissue from spongiform encephalopathy victims, infectivity is not destroyed. Furthermore, purification of infected tissue to concentrate the infectious fraction yields protein, not nucleic acid. While it remains possible that some highly stable nucleic acid remains hidden within the purified protein, this is seeming less and less likely as further experiments are done. The "prion hypothesis," as it is called, is now widely accepted, at least provisionally, by most researchers in the field. The most vocal proponent of the hypothesis, Stanley Prusiner, was awarded the Nobel Prize in 1997 for his work in the prion diseases.

A prion is an altered form of a normal brain protein. The normal protein has a helical shape along part of its length. In the prion form, a sheet structure replaces the helix. According to the hypothesis, when the normal form interacts with the prion form, its helical part is converted to a sheet, thus creating a new prion capable of transforming other normal forms. In this way, the disease process resembles crystallization more than typical viral infection, in which the virus commands the host's cellular machinery to reproduce more of the virus. Buildup of the sheet form causes accumulation of abnormal protein clumps and degeneration of brain cells, causing dementia and ultimately death.

The brain protein affected by the prion, called PrP, is part of the membrane of brain cells, but its exact function is unknown. It is composed of about 250 subunits, called amino acids, coded for by a gene on chromosome 20. Slight genetic differences, called polymorphisms, give rise to two slightly different normal protein forms: subunit 129 is a "methionine" in one form, but is "valine" in the other. A person may have all of one, all of the other, or a mixture of the two, depending on their genetic inheritance. Both forms have the normal helical structure, and function normally. However, susceptibility to prion conversion is influenced by subunit 129: a person with a mixture of forms is more resistant to conversion, and a person with all valine appears to be somewhat more susceptible than one with all methionine. Exposure to the infectious agent is, of course, still required for disease development. Prion diseases are not contagious in the usual sense, and transmission from an infected person to another person requires direct inoculation of infectious material.

Familial CJD, on the other hand, does not require exposure but develops through the inheritance of other, more disruptive mutations in the gene for the normal PrP protein. Researchers believe these mutations increase the likelihood that the protein will spontaneously "flip" to the sheet form; once created, these can then convert other normal-form molecules. The other two inherited human prion diseases, Gerstmann-Straussler-Scheinker disease and fatal familial insomnia, involve different mutations in the same gene.

The large majority of CJD cases are sporadic, meaning they have no known route of infection or genetic link. Causes of sporadic CJD are likely to be diverse and may include spontaneous genetic mutation, spontaneous protein changes, or unrecognized exposure to infectious agents. It is highly likely that future research will identify more risk factors associated with sporadic CJD.

More information on prion diseases (Creutzfeldt-Jakob disease, fatal familial insomnia, kuru)