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Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Neuroscience. 2nd edition. Sunderland (MA): Sinauer Associates; 2001.

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Neuroscience. 2nd edition.

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Box APrion Diseases

Creutzfeldt-Jakob disease (CJD) is a rare but devastating neurological disorder characterized by cerebellar ataxia, myoclonic jerks, seizures, and the fulminant progression of dementia. The onset is usually in middle age, and death typically follows within a year. The distinctive histopathology of the disease, termed “spongiform degeneration,” consists of neuronal loss and extensive glial proliferation, mainly in the cortex of the cerebellum and cerebrum; the peculiar spongiform pattern is due to vacuoles in the cytoplasm of neurons and glia. CJD is the only human disease known to be transmitted by inoculation (either orally or into the bloodstream) or inherited through the germline! In contrast to other transmissible diseases mediated by microorganisms such as viruses or bacteria, the agent in this case is a protein called a prion.

Observations dating back some 30 years suggested that CJD was infective. The major clue was a once obscure disease of sheep, called scrapie, which is also characterized by cerebellar ataxia, wasting, and intense itching. The ability to transmit scrapie from one sheep to another strongly suggested an infectious agent. Another clue came from the work of Carlton Gajdusek, a neurologist studying a peculiar human disease called kuru that occurred specifically in a group of New Guinea natives known to practice ritual cannibalism. Like CJD, kuru is a neurodegenerative disease characterized by devastating cerebellar ataxia and subsequent dementia, usually leading to death within a year. The striking similarities in the distinctive histopathology of scrapie and kuru, namely spongiform degeneration, suggested a common pathogenesis and led to the successful transmission of kuru to apes and chimpanzees in the 1960s, confirming that CJD was indeed infectious. The prolonged period between inoculation and disease onset (months to years) led Gajdusek to suggest that the transmissible agent was what he called a “slow virus.”

These extraordinary findings spurred an intensive search for the infectious agent. The transmission of scrapie from sheep to hamsters by Stanley Prusiner at the University of California at San Francisco permitted biochemical characterization of partially purified fractions of scrapie agent from hamster brain. Oddly, he found that the infectivity was extraordinarily resistant to ultraviolet irradiation or nucleases, treatments that degrade nucleic acids. It therefore seemed unlikely that a virus could be the causal agent. Conversely, procedures that modified or degraded proteins markedly diminished infectivity. In 1982, Prusiner coined the term “prion” to refer to the agent causing these transmissible spongiform encephalopathies. He chose the term to emphasize that the agent was a proteinaceous infectious particle (making the abbreviation a little more euphonious in the process). Subsequently, a half dozen more diseases of animals—including mad cow disease—and four more human diseases have been shown to be caused by prions.

Whether prions contain undetected nucleic acids or are really proteins remained controversial for some years. Prusiner strongly advocated a “protein only” hypothesis, a revolutionary concept with respect to transmissible diseases. He proposed that the prion is a protein consisting of a modified (scrapie) form (PrPSc) of the normal host protein (PrPC for “prion protein control”), the propagation of which occurs by a conformational change of endogenous PrPC to PrPSc autocatalyzed by PrPSc. That is, the modified form of the protein (PrPSc) transforms the normal form (PrPC) into the modified form, much as crystals form in supersaturated solutions. Differences in the secondary structure of PrPC and PrPSc evident by optical spectroscopy supported this idea. An alternative hypothesis, however, was that the agent is simply an unconventional nucleic acid-containing virus, and that the accumulation of PrPSc is an incidental consequence of infection and cell death.

A compelling body of evidence in support of the “protein only” hypothesis has emerged only in the past decade. First, PrPSc and scrapie infectivity copurify by a number of procedures, including affinity chromatography using an anti-PrP monoclonal antibody; no nucleic acid has been detected in highly purified preparations, despite intensive efforts. Second, spongiform encephalopathies can be inherited in humans, and the cause is now known to be a mutation (or mutations) in the gene coding for PrP. Third, transgenic mice carrying a mutant PrP gene equivalent to one of the mutations of inherited human prion disease develop a spongiform encephalopathy. Thus, a defective protein is sufficient to account for the disease. Finally, transgenic mice carrying a null mutation for PrP do not develop spongiform encephalopathy when inoculated with scrapie agent, whereas wild-type mice do. These results argue convincingly that PrPSc must indeed interact with endogenous PrPC to convert PrPC to PrPSc, propagating the disease in the process. The protein is highly conserved across mammalian species, suggesting that it serves some essential function, although mice carrying a null mutation of PrP exhibit no detectable abnormalities.

These advances notwithstanding, many questions remain. What is the mechanism by which the conformational transformation of PrPC to PrPSc occurs? How do mutations at different sites of the same protein culminate in the distinct phenotypes evident in diverse prion diseases of humans? Are conformational changes of proteins a common mechanism of other neurodegenerative diseases? And do these findings suggest a therapy for the dreadful manifestations of spongiform encephalopathies?

Despite these unanswered questions, this work remains one of the most exciting chapters in modern neurological research, and rightly won Nobel prizes in Physiology or Medicine for both Gajdusek (in 1976) and Prusiner (in 1997)


  1. Bueler H. , 6 Others Mice devoid of PrP are resistant to scrapie. Cell. (1993);73:1339– 1347. [PubMed: 8100741]
  2. Gajdusek D. C. Unconventional viruses and the origin and disappearance of kuru. Science. (1977);197:943–960. [PubMed: 142303]
  3. Gibbs C. J. , Gajdusek D. C. , Asher D. M. , Alpers M. P. Creutzfeldt-Jakob disease (spongiform encephalopathy): Transmission to the chimpanzee. Science. (1968);161:388–389. [PubMed: 5661299]
  4. Prusiner S. B. Novel proteinaceous infectious particles cause scrapie. Science. (1982);216:136–144. [PubMed: 6801762]
  5. Prusiner S. V. , Scott M. R. , DeArmond S. J. , Cohen G. E. Prion protein biology. Cell. (1998);93:337–348. [PubMed: 9590169]
  6. Rhodes, R. (1997) Deadly Feasts: Tracking the Secrets of a Terrifying New Plague. New York: Simon and Schuster.


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