In this post, I will focus on a group of diseases that is unique in its features: prion diseases. They are caused by misfolding of prion protein (see further), and their uniqueness relies on the mechanism of origin, which can be either sporadic (if it develops in the organism), hereditary (if inherited, implying a familial origin) or acquired (infectious/transmitted). Prion protein is encoded by PRNP gene, which plays an important role in the nervous system, by promoting spatial memory (information about environment and spatial orientation). Mutations in the PRNP gene determine misfolding of the protein, which in turn causes prion diseases (I recommend you to read this post about how DNA mutations predispose to diseases). Proteins are long chains of aminoacids that fold according to specific rules, and misfolding causes improper function of the protein. In nomenclature, the normal (properly folded) protein is called PrPC, while the misfolded version PrPSc and is commonly referred to as prion. A prion is able to induce misfolding of a normal PrPC, transforming it into another prion, in a cascade process. Until 2015, all prion diseases were thought to be caused by PrPSc, but then multiple system atrophy was discovered, which is hypothesized to be caused by misfolding of alpha-synuclein.

Human prion diseases occur in developed countries at a rate of 1 to 1.5 cases per million per year. For example, in the United States, about 400 cases of prion disease are diagnosed every year (on a population of 330 million).

Disease features

PrPSc forms aggregates outside cells in the central nervous system (in the brain), resulting in plaques that disrupt the normal tissue. This disruption is characterized by “holes” in the tissue that give a typical spongy architecture (from here the name spongiform encephalitis). This process determines an inflammatory response, although the disease can be incubated for up to 5 to 20 years. Once symptoms appear, the disease progresses rapidly, leading to brain damage and death. All known prion diseases are untreatable and fatal. Neurodegenerative symptoms  include convulsions, dementia, ataxia (balance and coordination dysfunction) and behavioural or personality changes.

Prion diseases: transmissible spongiform encephalitis

Prion diseases include a broad range of transmissible spongiform encephalitis (TSE). Of these, the most common is sporadic Jakob-Creutzfeldt disease, which comprises 85-90% of prion diseases. 10% to 15% are familial and less than 1% acquired. Other than Creutzfeldt–Jakob disease (CJD) and its variant (vCJD), prion-caused TSEs in humans are Gerstmann–Sträussler–Scheinker syndrome, “fatal familial insomnia” and kuru. Kuru, in particular, is an extremely rare TSE with a prevalence as high as 2% in women and children of some tribes in Papua Nuova Guinea and was caused by ritual cannibalism. This was a form – now forbidden – of respect and mourning towards dead relatives. While men used to eat muscles of corpses, women and children ate viscera and brain, the latter at risk of prionic infection.

In the animal world

In the animal world, TSEs include scrapie in sheep, chronic wasting disease (CWD) in deer, bovine spongiform encephalopathy (BSE) in cattle (commonly known as “mad cow disease”), and others. Because, as already mentioned, it is enough that a misfolded prion meets a normal PrPC to start the formation of aggregates, it is possible – although rare – cross-species contamination. For example, the human disease “variant Creutzfeldt-Jakob disease” is believed to be a zoonotic disease caused by the BSE agent. It is still unclear how the disease was transmitted to human, but the generally accepted hypothesis sees as cause the exposure to food contaminated by the bovine BSE agent. In the United Kingdom, over 180,000 cases of BSE have been confirmed in cattle between 1986 and October 2004, and from October 1996 to November 2004, 152 cases of (probable) vCJD have been reported in the United Kingdom, eight in France, two in Ireland and one each in Canada, Italy and the United States of America.

Therapy

There is no therapy able to cure TSEs, although recently some treatments were developed to delay the disease progression, including pentosan polysulfate, quinacrine, and amphotericin B. Immunotherapy provided the best results in fighting prion diseases: research is moving towards development of both vaccines against prions, and therapy based on prion-specific immune cells. These options result all in activation of the immune system, aiming to destruction of misfolded prion proteins. Physiologically, instead, the immune system remains silent against prion diseases because their cause originates from the organism and consequently is not seen as pathogenic by our surveillance system.

References

Groschup MH, Kretzschmar HA, eds. (2001). Prion Diseases Diagnosis and Pathogeneis. Archives of Virology. Suppl 16. New York: Springer.

Prusiner SB, Woerman AL, Mordes DA, Watts JC, Rampersaud R, Berry DB, Patel S, Oehler A, Lowe JK, Kravitz SN, Geschwind DH, Glidden DV, Halliday GM, Middleton LT, Gentleman SM, Grinberg LT, Giles K (2015). Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism. Proceedings of the National Academy of Sciences of the United States of America. 112 (38): E5308–17.

Robbins SL, Cotran RS, Kumar V, et al., eds. (1999). Robbins pathologic basis of disease. Philadelphia: Saunders.

Geschwind MD. (2015) Prion diseases. Continuum (Minneap Minn). Dec; 21(6 Neuroinfection disease): 1612–1638.

Burchell JT, Panegyres PK. Prion diseases: immunotargets and therapy. Immunotargets Ther. 2016;5:57-68. Published 2016 Jun 16. doi:10.2147/ITT.S64795