Author: Celine Tedja
Artist: Naomi Chung
Editor: Pelin Meric
Proteins are vital molecules in the machinery of cells. Therefore, having the correct and precise protein structures is crucial to ensuring properly functioning systems in the body. Even a slight error at such a molecular level can result in an undesirable complication. You have probably heard of the currently widely researched Alzheimer’s and Parkinson’s diseases, which are neurodegenerative disorders caused by the incorrect folding of proteins, resulting in irregular conformations of proteins. There are also less commonly known neurodegenerative disorders caused by protein misfolding, called prion diseases. However, scientists are still studying these diseases in depth to unravel more information about them.
Prion diseases are rare, fatal, and untreatable illnesses found in both humans and animals that cause progressive damage to the brain. They occur when normal prion proteins, primarily found in the brain, fold into abnormal structures. The actual purpose of these prion proteins and the mechanism by which they can misfold have yet to be discovered. Some examples of prion diseases include Creutzfeldt-Jakob disease, bovine spongiform encephalopathy (BSE), Gerstmann–Sträussler–Scheinker syndrome (GSS), fatal familial insomnia (FFI), scrapie, chronic wasting disease, and kuru. These disorders can be sporadic (occurring occasionally), genetic (inherited or due to mutation), or acquired (transmitted).
The term ‘prion’ was first coined in 1982 by Stanley Ben Prusiner, who worked at the Institute for Neurodegenerative Diseases at the University of California, San Francisco (UCSF). It is short for ‘proteinaceous infectious particles.’ He and his team were investigating the cause of scrapie disease. It was hypothesised that the agent was a virus; however, his research revealed that the purified sample contained no nucleic acid, which should have been present if the agent was a virus. Instead, a protein was found to be present in the sample. Prusiner won the 1997 Nobel Prize in Physiology or Medicine for his groundbreaking discovery.
The general mechanism that has been studied so far is that a naturally occurring prion protein called PrPC (Cellular Prion Protein) folds abnormally to form an irregular conformation called PrPSc (Scrapie Prion Protein). This may occur sporadically or due to genetic mutations of the genes regulating the protein. PrPSc can also be acquired through ingestion or other types of exposure since it is known to be infectious. Once present in the body, PrPSc will amplify the misfolding of other normal prion proteins. Furthermore, a group of PrPSc will accumulate and self-assemble to form insoluble aggregates (clumps) called amyloids. This phenomenon is called protein aggregation, which causes tissue damage and cell death. In this case, amyloids form vacuoles in the brain and neurons, thus making them spongy.
Prion diseases may be diagnosed in the same way as other brain disorders. Some methods include MRI (Magnetic Resonance Imaging) scans of the brain, collecting samples of fluid from the spinal cord, electroencephalograms, which analyse brain waves by placing electrodes on the scalp, and blood tests. They can also be confirmed by taking a sample of brain tissue during a biopsy or after death.
Currently, several research institutions are developing techniques to learn more about prion diseases. The Rocky Mountain Laboratories (RML) in Hamilton, Montana, have been culturing cerebral organoids (mini-brain models) in incubators to study how prion diseases affect the brain. Cerebral organoids are small groups of human brain cells derived from stem cells, and they recapitulate many aspects of the real, complex human brain. Another way to analyse protein misfolding is by using microplate readers capable of detecting fluorescence and certain fluorescent dyes. These dyes bind to amyloid aggregates, which results in an increased fluorescence signal. By monitoring the changes in fluorescence intensity over time, researchers can observe the kinetics of protein aggregation. These methods can therefore be used to potentially prevent advances in protein misfolding and develop therapies for prion diseases.
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