Refolding the Script: Can We Stop the Infectious Momentum of Prions?
By Mackenzie Coleman, Mechanical Engineering, 2019
In 1997, Stanley Prusiner’s discovery of prions earned him a Nobel Peace Prize. This honor is indicative of the immense importance of these molecules. The term prion is an abbreviation of “proteinaceous infectious particle.” Thus, prions are protein-based molecules that are able to affect the structures of other molecules.
More specifically, prion proteins (often referred to as PrPs) are proteins that have folded improperly. They induce normal proteins to misfold as well, forming insoluble aggregate clumps that interfere with cell functions. Eventually the cell dies. When this prion misfolding occurs exponentially, it results in the rapid spread of cell death and this manifests as neurodegenerative disease.
One study suggests that protein misfolding is an inevitable result of life and imperfect cell function. However, humans have evolved biophysically to minimize the cost of transcription and misfolding mistakes. Certain evolutionary breakthroughs in species would not be possible without these mistakes, and thus prions are crucial to evolution. Now that humans have evolved and developed a functional society, however, the infectious nature of prions is perhaps more threatening than advantageous.
Prion diseases are unique in that they can aggressively attack neurons in the central nervous system and cause death within a year. There is currently no cure for prion diseases because we do not yet have the biotechnology to stop their infectious misfolding and protein accumulation. Further, these prion diseases can have an incubation time of over a decade, which makes them harder to study and eliminate as they lay dormant. These diseases have been found to occur either randomly or from a few consistent sources. There famously was an outbreak of the prion disease called Kuru in Papua New Guinea in the middle of the 20th century that was caused by cannibalism. The consumption of deceased bodies was a traditional funeral practice for the purpose of absorbing life force. Residents would unknowingly eat infected human meat and their proteins would be irrevocably misaligned during its digestion. Kuru clearly displays just how infectious PrPs are, and how susceptible proteins are to being folded incorrectly.
Fortunately, awareness about the source of Kuru has increased, and consequently, Kuru has become virtually nonexistent. Prion diseases are spread through sources other than cannibalism, however. Mad cow disease (known formally as bovine spongiform encephalopathy or BSE) has caused widespread bovine deaths and is linked to a variant disease in humans called Creutzfeldt–Jakob disease (CJD). CJD is caused by consuming meat infected with BSE and kills about one in one million people worldwide.
Some prion diseases appear to be familial, passed genetically or by infection from parents to offspring. Others are transferred iatrogenically, through contaminated human growth hormones or surgical equipment and procedures. Ultimately, sporadic infections are the most frequent way PrPs form in humans. More common diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and multiple system atrophy (MSA) can develop very suddenly and are linked to prion replication, but do not have an equivalent infection in animals. The idea that these diseases may be prion-like has gained a lot of traction, but the actual proteins that are involved cannot be transmitted among organisms, and thus they are not true prions. Prion-based research may be useful to develop therapies for these diseases, however, as they are also fatal neurodegenerative states that are currently untreatable.
Research is under way to reverse what seems to be an inevitable spread of infection within organisms. RNA interference (RNAi) is biotechnology that involves gene silencing that would potentially help to stop the replication of infected protein folding patterns. Other studies have looked at treatment at a very small drug molecule scale. Small molecule drugs are typically the size of a few nanometers, or the order of 10–9 m. This small scale is critical as larger treatment options, like antibodies, are discarded as they are too large to fit inside blood vessels in the brain. An indubitable truth of these prion-like diseases is that they can all be better understood in the context of prions and similar proteins. Emory University researcher Larry Walker expressed this thought in Scientific American: “By focusing on the simplicity of the molecular mechanism, you can make sense of a lot of seemingly disparate diseases.” Definitive methods for stopping this mechanism are not yet clear, but there is promising evidence that the rapid fate of prion misfolding will someday be reversed.
Nature Reviews Genetics (2009). DOI: 10.1038/nrg2662.