A Brief History of Prions and the TSEs

The term “prion” was first introduced in 1998 by Dr. Stanley Pruisiner in his Nobel Prize-winning paper of the same title (Pruisiner, 1998).  Coining a shortened hybrid of the term “proteinaceous infectious particle,” Pruisiner posited that prions were transmissible misfolded forms of proteins that cause a set of neurodegenerative, fatal “prion diseases” known as Transmissible Spongiform Encephalopathies (“TSEs”) (Pruisiner, 1998). Bovine Spongiform Encephalopathy (commonly known as Mad Cow Disease), sheep Scrapie, and human Creutzfeldt-Jakob Disease (“CJD”) are the most notable such TSEs and are marked by a slow onset of degenerative neurological symptoms including tremors, ataxia, dementia, loss of muscle control, and behavioral changes ultimately deteriorating to severe myoclonus and death (Belay, 1999).

            Public discourse involving TSEs has largely revolved around fear of the zoonotic transfer of Mad Cow Disease through the human agricultural industry (Belay, et al, 2005).  Since its first recorded case of widespread outbreak in the United Kingdom in 1986, it is estimated that more than 750,000 infected cows were slaughtered and subsequently consumed by millions of UK residents (Belay, et al, 2005).  Moreover, cases of BSE have been discovered in 22 additional countries since 1986, including cases in North America (Belay, et al, 2005).  Such numbers are particularly alarming given the strong evidence indicating cross-species transmission of this infectious agent to humans thereby causing a variant form of CJD (“vCJD”) and a number of reported cases of human death from vCJD in the UK (Belay, et al, 2005).

            According to the CDC, the rate of CJD occurrence in the U.S. is approximately 1-1.5 cases per 1 million per year, though risk increases with age and the annual rate jumps to 3.4 cases per million in persons over 50 (CDC).  Moreover, there were approximately 478 deaths due to CJD in the U.S in 2013, a significant increase from the preceding year of 380 (CDC).  While the slow onset of symptoms have been discussed, I will close by discussing certain detection methods in humans for prion diseases.

Clinical Presentation and Detection

            This entire class of prion diseases came to be known as Transmissible Spongiform Encephalopathies (“TSEs”), so called due to the characteristic sponge-like appearance of infected neuronal tissue due to holes in the brain cortex (Belay, 1999).  The four characteristic features of all prion disease include (1) spongiform tissue change, (2) neuronal loss, (3) astrocytosis, and (3) formation of amyloid plaques (Belay, 1999). 

            Prion diseases such as CJD can be diagnosed using neuropathological techniques (Global Surveillance).  One problem with diagnosis is that a diagnosis with 100% certainty can only be made upon death by laboratory testing of brain matter (using techniques such as immunocytochemical tests, western blotting, or confirmation of presence of scrapie-associated fibrils) (Global Surveillance).  Probable diagnoses can be made using clinical symptoms, including rapid and progressive dimentia and myoclonus coupled with either MRI abnormalities or a posirive 14-3-3 CSF test (Global Surveillance).

This image shows a human brain lesion after infection from sCJD strain of Crutzfeld-Jakob Disease in a small region of the thalamus.  B shows a human brain lesion after infection from a more virulent Japanese CJD strain with more widespread deposits in the hipoccampus.  Photos taken from electron microscopy (Manuelidis 2003).

This photo, taken with electron microscopy with silver intensified ultrasmall immunogold labeling of PrP, shows amalgamated lesions in a human brain with the lined pattern of an amyloid fiber formation in characteristic criss-crossing bundles (Manuelidis 2007).

Pruisner, Stanley B., 1998.  Prions. Proceedings of the National Academy of Sciences of the United States of America.  95(23): 13363-13383.

Belay, Ermias, 1999.  Transmissible Spongiform Encephalopathies in Humans.  Annu. Rev. Microbiol.  53: 283-314.

Belay, Ermias, and L. Schonberger, 2005.  The public health impact of prion diseases.  Annu. Rev. Public Health.  26: 191-212.

CDC: http://www.cdc.gov/prions/cjd/occurance-transmisison.html

Global Surveillance, diagnosis, and Therapy of Human Transmissible spongiform Encephalopathies: Report of WHO consultation, February 9-11, 1998, Geneva, Switzerland

Manuelidis, Laura, and Z. Yu, 2003.  Virus-like interference in the latency and prevention of Creutzfeldt-Jakob disease.  Proceedings of the National Academy of Sciences of the United States of America.  100(9): 5360-5365.

Manuelidis, Laura, Z. Yu, N. Barquero, and B. Mullins, 2007.  Cells infected with Scrapie and Creutzfeldt-Jakob disease agents produce intracellular 25-nm virus-like particles.  104(14): 1965-1970.