By: Caroline Wechsler
Since their formal discovery in 1982, prions have been a mysterious scourge. Very small and not well-defined, these mysterious disease-causing agents are the source of great confusion and grief in the scientific world. But some recent discoveries are shedding new light on how to conceptualize and potentially treat such diseases.
What are Prions?
The term prion stands for “proteinacious infectious particle” (1). Prions are small, misfolded proteins that are able to be spread by inducing other proteins to misfold in similar ways (2). Prion protein exists in all humans, but in a normal state called the cellular prion protein, or PrPC (1). However, when this prion misfolds, it becomes the version of prions that we typically think of – disease-causing and harmful (1).
The first observation of prion-caused diseases was in the 1730s in Scotland: scrapie, a neurodegenerative disease found in sheep and goats (3). The disease was originally thought to be viral, and it was not until in-depth analysis of Kuru disease in the 1950s revealed misfolded proteins to be the main cause that this hypothesis was disputed (3). In the 1980s, prions became the focus of much media and scientific attention when several cases of Creutzfeldt-Jakob disease, a prion-caused condition, were associated with contamination of surgical instruments and growth hormone injections (4). The full prion hypothesis was put forth by Stanley Prusiner in 1982; though the idea was not completely new at that point, it had never been fully outlined and formalized (3). He went on to win the Nobel Prize in 1997 for this discovery (3).
Prions have been a source of controversy since Prusiner first coined the term in 1982. The reason for this controversy is that the notion that a protein would be able to reproduce itself without a DNA or RNA intermediate step was previously unheard of, and goes against the central dogma of molecular biology (DNA to RNA to protein).4 Because prions seem not to contain any genetic material, which essentially all other infectious agents (including viruses) do contain, the idea was radical (4). However, increasing evidence over the past few decades seems to solidify the idea that prions do exist, and are in fact the cause of several previously unexplainable diseases.
Prions and Disease
Prions are known to cause disease in many organisms, including humans. These diseases affect the nervous system, and are associated with impairment in brain function and changes in personality (5). Prion diseases have several primary causes: there are a few genes which have been associated with hereditary transmission of prion diseases; prions have been known to be transmitted through contamination; and some prion conditions occur spontaneously in humans (5).
These diseases are very rare, with only about 300 cases being reported every year in the US.6 Perhaps the most well-known example is Creutzfeldt-Jakob disease (CJD), or “mad cow” disease. This disease caused a scare in 2003 when several cases were discovered world wide, and were tied to contaminated cattle feed (hence the term mad cow disease) (7). The disease is characterized by progressive dementia, muscle spasms, and akinetic mutism (a loss of will to move) (2). Another example is Kuru, a rare neurodegenerative disease found only in the Fore tribe in New Guinea, transmitted through the cannibalistic behavior of eating human brains (4).
Recently, though, other neurodegenerative diseases have potentially been shown to be associated with prions. Scientists now believe that many neurodegenerative disorders, such as Alzheimer’s, Huntington’s, and Parkinson’s diseases (8). A study published in September of last year which conducted autopsies of eight CJD patients found that these patients’ brains showed diagnostic signs of Alzheimer’s disease, though all the patients would have been too young to show these symptoms (8). This suggests that Alzheimer’s disease is potentially transmissible and caused by small, misfolded proteins such as prions. Additionally, just this past year a different neurodegenerative disease called multiple system atrophy, or MSA, was also found to be associated with prions (9). Though transmission represents a small percentage of the cases of prion diseases, such a discovery is promising because it offers the potential for new diagnostic and therapeutic techniques and advancements.
NEW TREATMENT HOPES
Currently, there are no specific treatments that have been proven to reliably cure prion diseases (2) The only therapy available for patients with CJD, Kuru, and other prion-caused diseases is medical management in order to reduce discomfort as the disease progresses (6). In this light, new technologies for treating this family of diseases is a priority.
Part of the problem with prion diseases is that they advance remarkably quickly; most CJD patients succumb to the disease within 4-5 months, and very few live longer than a year (2). What scientists are primarily searching for is something which can at least slow, if not completely stop, the buildup of the toxic, misfolded proteins.
In the past decade, there has been some advancement: a few research groups have reported finding compounds which slow the propagation of prions in mouse models. Four different small molecules – Compound B (discovered in 2007), Anle138b (discovered in 2013), and LIN5044 (discovered in 2015) – have been shown to extend mouse life-span by at least two times (10).
The idea behind using small molecules as therapeutic tools is that they fill a pocket in a protein receptor, preventing it from being active. However, this was originally thought to be useless with prions because they involve protein-protein surface interactions rather than small surface-area interactions (10). What researchers are now looking for are molecules which bind to and stabilize the non-pathogenic form of the protein in question, and prevent it from changing to a toxic conformation (11).
None of these compounds will be a magic bullet for prion diseases. All four small molecules display a common limitation: they work well with one animal-specific strain of prion, but none has been yet found to be effective against the human forms of the disease (10). However, the real advancement from the discovery of these compounds is the principle and basic structure of the compounds that seem to work, which scientists believe they can use to look for compounds which will be effective in humans.
Looking forward, it seems clear that exact knowledge of prion diseases and how to cure them is still out of reach. But armed with new information about what sorts of diseases can be classified as prion-caused, and some potential new small molecule solutions, we seem to be edging towards a better understanding of how prions cause disease and how to stop them.
Caroline Wechsler ‘19 is a freshman in Weld Hall.
 “What are prions?” Prion alliance. 26 Nov 2013. Web.
 “Creutzfeldt-Jakob Disease, Classic (CJD).” Centers for Disease Control. 6 Feb 2015. Web.
 Liberski, Pawel. “Historical overview of prion diseases: a view from afar.” 2012. Folia Neuropathological. 50 (1): 1-12.
 “Prions: On the Trail of Killer Proteins.” Genetic Science Learning Center. 2016. Web.
 “Prion Disease.” Genetics Home Reference. Jan 2014. Web.
 “Prion Diseases.” Health Library. Johns Hopkins Medicine. 2016. Web.
 “The spread of mad cow disease.” CNN. Cable News Network. 23 Dec 2003. Web.
 Kwon, Diana. “Are prions behind all neurodegenerative diseases?” Scientific American. 1 Nov 2015. Web.
 Rettner, Rachel. “Another Fatal Brain Disease May Come from the Spread of ‘Prion’ Proteins.” Live Science. 31 Aug 2015. Web.
 Torrice, Michael. “Slowing Prions With Small Molecules.” 7 Sept 2015. Chemical and Engineering News. 93(35): 37-39.
 “Small molecule therapeutics.” MRC Prion Unit. Medical Research Council. 2016. Web.
Categories: Spring 2016