As with many pathogens, the discovery of “Prion Diseases” preceded the discovery of prions themselves and, thus, led to the search for the causal agent responsible for this transmissible spongiform encephalopathy family of diseases. Between 1957 and 1976, Dr. Carleton Gajdusek studied a transmissible, always fatal, neurodegenerative disease called Kuru in the Fore tribe of Papua New Guinea (Gajdusek, et al., 1967). By successfully transmitting this disease to chimpanzees through cerebral injection of diseased brain tissue, Gajdusek elucidated that the disease was transmissible and had been spread through the Fore population as a result of their endocannibalistic funeral rituals during which diseased brain tissue was consumed (Gajdusek, et al., 1967). Kuru was later linked to other known diseases in animals and human populations due to their similar pathology, specifically Creutzfeldt-Jakob Disease in humans and Scrapie in sheep (Belay, 1999).
It was not until 1997 that, Stanley Pruisiner posited the discovery of the infectious agent cause of TSEs (Pruisiner, 1998). It was then that he laid out the Prion Hypothesis that a misfolded, protease-resistant, form of the Protein PrP was the agent that caused TSEs, and that that misfolded protein could be transmitted to other organisms and cause infectious misfolding (Pruisiner, 1998). Though both forms are encoded by the same PrP gene sequence and, therefore, contain the same polypeptide sequence, normal cellular PrP (PrPc) is converted into its misfolded form (PrPsc) post-translationally (Pruisiner, 1998).
Transmissibility
A significant
attribute of prions is their ability to spread in spite of modern tools and
methods ordinarily thought to prevent diseases transmission. The 1980s-1990s outbreak of Mad Cow Disease
in the UK was later shown to be the result of agricultural feeding methods
whereby tissue of infected animals was reconstituted into the feed of other
livestock (Belay, 1999). In addition,
numerous cases of transmission of CJD have been reported, ranging
from corneal graft transplants, injection of pituitary-derived human growth
hormone, and receipt of infected dura mater grafts (Belay, et al., 2005). Relatedly, prion proteins have been recently
detected in urine-derived human fertility products, suggesting a need for additional
purification processes in their production (Van Dorsselaer et al., 2011). There have also been cases of transmission
through sanitized neurosurgical equipment, which has led to heightened
standards of sanitization (Belay, et al., 2005). Perhaps most chillingly, one lab recently
reported that transgenic mice bred to overexpress PrPc have
developed PrPsc and prion disease upon exposure to aerosolized
prions, which may warrant additional safety precautions surrounding prions
(Haybaeck et al., 2011).
Misfolded PrPsc
are able to bind to normal PrPc and convert them to PrPsc (Pruisiner,
1998). Recent research indicates that the conversion of PrPc to PrPsc
may take place on lipid rafts (Agostini et al., 2013). In a manner that has been likened to
crystallization, misfolded PrP act as seeds whereby their misfolded b-sheet monomers form
intermolecular hydrogen-bonds with PrP monomers, thereby forming aggregates of
ubiquitinated proteins that cause lesions in the brain (Chaudhuri, et al.,
2006). This model involves the formation
of b-linkages with pleated
sheet strands from PrPsc being inserted into pleated sheets of
nearby PrPc, leading to the hydrogen bond formation (Chaudhuri, et
al., 2006). An alternative model
suggests environmental stressors such as genetic mutations, oxidative stress,
alkalosis, acidosis, pH shift, or osmotic shock as external stimuli that alters
the native confirmation of PrPc (Chaudhuri, et al., 2006). Notably, this alternative hypothesis does not
account for the slow progression of PrPc into PrPsc. A final model—and one that may also serve a
model for future treatment—suggests the presence of chemical chaperone
intermediaries that interact with the PrP conformation (Chaudhuri, et al.,
2006).
Current Treatment and Preventive Measures
Whether genetic, sporadic, or acquired, prion diseases in humans are always fatal and currently untreatable (Prion Alliance). Because they are unlike other infectious agents that have been studied and for which treatments have been developed--they do not have DNA and are in fact differently folded host proteins--the optimal strategy for treatment is yet unclear (Prion Alliance). Scientists are, however, investigating different treatment methods. Researchers have developed small molecule drugs that work on some mouse pron strains (Prion Alliance). In addition, there may be promising research around development of antibodies to the misfolded proteins, but the complication remains that the prions are simply differently-folded forms of native proteins, which may cause complications in the administration of drugs (Prion Alliance).
Because no treatments have been yet developed to cure prion diseases in humans, the focus must remain on prevention. In light of the methods of disease spread discussed earlier, such prevention efforts have focused around properly sterilizing medical equipment, particularly such equipment that is used on human brains (http://www.hopkinsmedicine.org/healthlibrary/conditions/nervous_system_disorders/prion_diseases_134,56/). In addition, proper screening methods for those who may already have prion diseases are needed to prevent those individuals from donating organs (Id.). Finally, because of the zoonotic transfer of the disease from cows to humans, proper handling and screening of livestock is critical (Id.).
Because no treatments have been yet developed to cure prion diseases in humans, the focus must remain on prevention. In light of the methods of disease spread discussed earlier, such prevention efforts have focused around properly sterilizing medical equipment, particularly such equipment that is used on human brains (http://www.hopkinsmedicine.org/healthlibrary/conditions/nervous_system_disorders/prion_diseases_134,56/). In addition, proper screening methods for those who may already have prion diseases are needed to prevent those individuals from donating organs (Id.). Finally, because of the zoonotic transfer of the disease from cows to humans, proper handling and screening of livestock is critical (Id.).
Recommendations: Can These Treatments and Measures Be Effective?
The tragedy remains that there is no effective cure or treatment for prion diseases. As a result, the focus on screening and prevention of disease spread through infected tissue appears to be the most pragmatic approach to prevention measures at this time. In particular, maintenance of proper agricultural and livestock practices to prevent zoonotic transfer from diseased meat will remain a critical component. The USDA assures the public that US livestock practices are safe from bovine spongiform encephalitis (BSE), citing the existence of many systematic safeguards and removal of "specified risk materials" from the human food chain, which could include non-ambulatory cattle or cattle displaying neurological symptoms (http://www.usda.gov/wps/portal/usda/usdahome?contentid=BSE_FAQs.xml). In addition, because of the mad cow outbreaks in other counries like the UK, the U.S. restricts any imports of ruminants and ruminant products from at-risk countries (Id.). Such preventative measures, on the exposure end, seem advisable and effective.
Notably, these measures have not been fool-proof. Indeed, in 2012, a confirmed case of BSE was reported in California (Id.). Prior to that, the USDA confirmed three additional cases 9 years prior (Id.). Unfortunately, the nature of the disease is such that presence in one cow may indicate presence in other cows, which is worrisome and presents the need for more effective and rapid screening practices of livestock and livestock products.
As to the development of actual treatments, however, I believe more research into the actual disease-causing agent of prion diseases themselves is greatly needed. Certainly, the development of a test for prion disease is needed. Beyond that, however, agreement as to the true source of the TSEs must occur.
Indeed, Pruisiner's theory of the infectious protein both contravenes the "central dogma" of molecular biology that the transfer and reproduction of biological information requires programmed information in the form of nucleic acids. Moreover, his model also fails to meet the Koch Postulates typically necessary to establish a causal relationship between an agent and a disease (Manuelidis 2007). An absence of detectable prions in material that is demonstrably infectious when injected into healthy organism brain tissue is a notable exception to the first criterion (Manuelidis 2007).
In sum, the current approach to treatment and prevention is really only the latter. Continued betterment of such prevention techniques, including careful vigilance over U.S. agricultural feeding practices and imported meat products/cattle is essential, as are the sterilization procedures in medical environments. However, for those prion diseases not caused by infected consumption, such as familial CJD, future treatments will rely on a better understanding of how prions truly spread.
Notably, these measures have not been fool-proof. Indeed, in 2012, a confirmed case of BSE was reported in California (Id.). Prior to that, the USDA confirmed three additional cases 9 years prior (Id.). Unfortunately, the nature of the disease is such that presence in one cow may indicate presence in other cows, which is worrisome and presents the need for more effective and rapid screening practices of livestock and livestock products.
As to the development of actual treatments, however, I believe more research into the actual disease-causing agent of prion diseases themselves is greatly needed. Certainly, the development of a test for prion disease is needed. Beyond that, however, agreement as to the true source of the TSEs must occur.
Indeed, Pruisiner's theory of the infectious protein both contravenes the "central dogma" of molecular biology that the transfer and reproduction of biological information requires programmed information in the form of nucleic acids. Moreover, his model also fails to meet the Koch Postulates typically necessary to establish a causal relationship between an agent and a disease (Manuelidis 2007). An absence of detectable prions in material that is demonstrably infectious when injected into healthy organism brain tissue is a notable exception to the first criterion (Manuelidis 2007).
In sum, the current approach to treatment and prevention is really only the latter. Continued betterment of such prevention techniques, including careful vigilance over U.S. agricultural feeding practices and imported meat products/cattle is essential, as are the sterilization procedures in medical environments. However, for those prion diseases not caused by infected consumption, such as familial CJD, future treatments will rely on a better understanding of how prions truly spread.
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Prion Alliance: http://www.prionalliance.org/2014/02/04/what-are-the-potential-treatments-for-prion-disease/
Prion Alliance: http://www.prionalliance.org/2014/02/04/what-are-the-potential-treatments-for-prion-disease/
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