Perilous Prions

PDB 1dx0 EBI
Image from Wikimedia Commons of a prion

Our cells make proteins constantly. Each day our bodies produce millions and millions of proteins that help our bodies function. Proteins do so much for our bodies- they accelerate chemical reactions, provide structure, protect against disease, help the cell respond to stimuli, and transport substances.There is no debate that proteins are vital to our daily existence, so that begs the question- what happens when proteins don’t function like they are supposed to?

One type of protein that can be lethal when misfolded is the Prion Protein (PrPC). It functions on the surface of neuron cells in the brain and assists at synapses- which are junctions where neurons send messages to each other. However, sometimes a mutation in the gene that codes prion proteins or an inherited hereditary flaw can lead to an incorrect coding of the amino acids in the prion protein. This creates a prion (PrPSc). The only difference between the prion protein and the prion is the replacement of a single amino acid. This amino acid can differ depending on the disease. For example, in familial Creutzfeldt-Jakob’s Disease, Glutamic Acid is replaced by Lysine. This single change causes the entire protein to misfold. So, what happens next? You would think that the body has some sort of mechanism to protect against an error that seems so simple, right? You would be correct.

After the prion is coded in the primary structure, it enters the secondary structure and forms a molten globule shape where it is misfolded because of the amino acid errors. This misfolded protein is recognized by the body as incorrect and sent to be repaired by chaperone catalysts, if the protein isn’t corrected here, it is sent to proteases (which are enzymes that break down proteins). However, this is where PrPSc differs from your ‘normal’ abnormal protein. Prions have resistance to protease proteins. The beta-pleated sheets in prions make them difficult to break down. Normal prion proteins have 43% alpha-helices and 3% beta-pleated sheets in their secondary/tertiary structure. However, the incorrect amino acids in the prion change the molecular interactions between molecules creating a prion which has only 30% alpha-helices and a whopping 43% beta-pleated sheets sheets (for more information). This structural error allows prions to persist in the bodies that it inhabits. This remarkable trait is furthered by prions’ ability to create other misfolded proteins, and that is really not a good thing for their hosts.

CSIRO ScienceImage 626 Mad Cow Disease or bovine spongiform encephalopathy BSE
Shows the brain of a cow inflicted with bovine spongiform encephalopathy.
Image from Wikimedia Commons

The white areas are cysts. Misfolded prion proteins cause spongiform encephalopathy (“sponge-like brain disease”). These prions will aggregate on the membrane of neurons forming large plaques that are toxic to brain tissue. This will cause cells to perform apoptosis (programmed cell death), forming cysts in the brain that give it a spongy look. There are several diseases that result from spongiform encephalopathy, such as Creutzfeldt-Jakob’s Disease (CJD), Kuru, Mad Cow Disease, and Fatal Familial Insomnia. Symptoms include poor memory, behavioral changes, muscle weakness, dementia. All progress to death. You would think that these horrible diseases would affect only the unfortunate individuals who develop prions, however prions also have a remarkable infectious capability. Prions can spread from individual to individual through eating meat/flesh that contains prions, contamination of medical equipment, blood donations, feces, saliva, urine, and indirectly through environmental contamination of soil, food, or water.

One famous instance of this infectious property occurred in Papua New Guinea. In the mid-twentieth century, a tribe in the Eastern Highlands of Papua New Guinea was severely affected by a cultural funeral ritual in which women and children consumed the brains of the deceased relatives as a way to show respect. This cannibalism allowed for the rapid spread of kuru amongst the tribe. At its height in the 1950s, the disease was killing 2% of the tribe per year as their brains slowly rotted. However, this allowed natural selection to run its course. The community that was affected the worst by the disease developed a variation that protects them from developing prions and getting the kuru disease. They are currently the only population in this world to have such an adaptation, and researchers are racing to capitalize on it to advance treatments for similar degenerative diseases.

One such study has been successful in laboratory trials at significantly increasing the lifespan of lab rats infected with spongiform encephalopathy. Dr. Sonia Vallahb with the Broad Institute of Harvard and MIT has developed a treatment that lowers prion proteins in an animal. A single dose can reverse symptoms of the disease even after brain cysts have formed. “While there are still many steps ahead,” said Vallabh, “these data give us optimism that by aiming straight at the genetic heart of prion disease, genetically targeted drugs designed to lower prion protein levels in the brain may prove effective in the clinic.” Even though this experiment and many of the like are still in their elementary phases, many researchers are looking to a bright future where misfolded proteins are not the end of one’s life.

About Mr. Mohn

Biology Teacher

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