Prion
The word prion first appeared in 1982, coined by Stanley B. Prusiner to describe a proteinaceous infectious particle. This term combines the words protein and infection to highlight its unique nature. Unlike viruses or bacteria, these particles contain no nucleic acids such as DNA or RNA. They exist solely as misfolded proteins that induce folding problems in normal variants of the same protein. The process leads directly to cellular death through self-propagation without genetic material. These proteins can misfold sporadically, due to genetic mutations, or by exposure to an already misfolded protein. The resulting abnormal three-dimensional structure allows them to propagate misfolding in other proteins. All known prion diseases in mammals affect the structure of the brain or other neural tissues. These diseases are progressive, have no known effective treatment, and are invariably fatal.
Normal prion protein PrPC contains 209 amino acids in humans with one disulfide bond. It has a molecular mass of approximately thirty-five thousand daltons and a mainly alpha-helical structure. This form is not sedimentable meaning it cannot be separated by centrifuging techniques. The infectious isoform called PrPSc always causes prion disease and has a higher proportion of beta-sheet structure instead of the normal alpha-helix. Several highly infectious brain-derived PrPSc structures were discovered using cryo-electron microscopy. Another brain-derived fibril structure isolated from humans with Gerstmann-Straussler-Schienker syndrome was also determined. High-resolution structural analyses reveal features that correlate with prion infectivity. In the prion amyloids individual PrP molecules stack via intermolecular beta sheets. The glycolipid anchors and asparagine-linked glycans project outward from the lateral surfaces of the fiber cores when present. Often PrPSc binds to cellular membranes via its array of glycolipid anchors but sometimes fibers dissociate from membranes. They accumulate outside of cells in the form of plaques. The end of each fiber acts as a template onto which free protein molecules may attach allowing the fiber to grow.
The first hypothesis explaining how prions replicate assumed a single PrPSc molecule binds to a single PrPC molecule. Manfred Eigen showed this model requires PrPSc to increase conversion rates by around ten to the power of fifteen. This problem disappears if PrPSc exists only in aggregated forms like amyloid where cooperativity acts as a barrier. Infectious monomeric PrPSc has never been isolated despite considerable effort. An alternative model assumes PrPSc exists only as fibrils where ends bind PrPC and convert it into PrPSc. If this were all then quantity would increase linearly forming ever longer fibrils. But exponential growth of both PrPSc and infectious particles is observed during disease. This occurs because fibril breakage creates new growing ends. A mathematical solution for exponential growth resulting from combined fibril growth and breakage was found. The rate depends largely on the square root of the PrPC concentration. In vivo data on prion diseases in transgenic mice match this prediction. Researchers at Dartmouth College discovered that host cofactor molecules are necessary to form PrPSc with high infectivity in vitro. Protein-only PrPSc molecules appear to lack significant levels of biological infectivity without these cofactors.
Prions cause neurodegenerative disease by aggregating extracellularly within the central nervous system to form plaques known as amyloids. These disrupt normal tissue structure creating holes with resultant spongy architecture due to vacuole formation in neurons. Other histological changes include astrogliosis and absence of an inflammatory reaction. While incubation periods for human prion diseases range from five to twenty years or more symptoms progress rapidly once they appear. Neurodegenerative symptoms can include convulsions dementia ataxia balance dysfunction and behavioral or personality changes. Many different mammalian species can be affected since the prion protein PrP is very similar in all mammals. Due to small differences in PrP between species transmission from one species to another is unusual. Human variant Creutzfeldt-Jakob disease is thought to be caused by a prion typically infecting cattle causing bovine spongiform encephalopathy. This strain transmits through infected meat. All known prion diseases remain untreatable and fatal until 2015 when a prion form of alpha-synuclein linked to multiple system atrophy emerged. The precise structure remains unknown though they can form spontaneously by combining PrPC homopolymeric polyadenylic acid and lipids.
Prion diseases arise in three ways: acquired familial or sporadic. Primary infection methods involve ingestion of PrPSc deposited in the environment through dead animal remains urine saliva and other body fluids. They may linger in soil by binding to clay and other minerals. A University of California research team provided evidence that infection occurs from prions in feces. Since animal excrement surrounds water reservoirs manure fertilizes many crop fields raising possibilities for widespread transmission. In 2015 researchers at The University of Texas Health Science Center found plants act as vectors for prions. When hamsters ate grass growing where a deer with chronic wasting disease was buried they became ill. These findings suggest prions enter food chains via plants eaten by herbivores completing the cycle. Overwhelming evidence shows prions resist degradation and persist in the environment for years. Soil-bound prions remain at stable or increasing levels suggesting accumulation in nature. One 2015 study found repeated drying and wetting may render soil bound prions less infectious depending on soil type. Effective decontamination requires protein hydrolysis or destruction of tertiary structure using agents like sodium hypochlorite or sodium hydroxide.
In the 18th and 19th centuries exportation of sheep from Spain coincided with scrapie causing animals to lie down bite feet rub backs against posts fail to thrive stop feeding and become lame. This likely represents the first recorded transmissible spongiform encephalopathy. Carleton Gajdusek began research in the 1950s showing kuru could transmit to chimpanzees winning the 1976 Nobel Prize. During the 1960s radiation biologist Tikvah Alper and biophysicist John Stanley Griffith developed hypotheses that these diseases stem solely from proteins. Griffith proposed three ways a protein could be a pathogen including abnormal forms converting normal proteins into their own shape. In 1982 Stanley B. Prusiner announced his team purified the hypothetical infectious protein though isolation took two more years. The protein was named a prion for proteinaceous infectious particle derived from protein and infection. When discovered Griffith's hypothesis that an abnormal host protein converts other proteins became dominant theory. Prusiner received the Nobel Prize in Physiology or Medicine in 1997 for this work. Francis Crick recognized potential significance of the Griffith protein-only hypothesis in his second edition of Central dogma published in 1970.
Prion-like domains appear in various mammalian proteins implicated in age-related neurodegenerative disorders like amyotrophic lateral sclerosis frontotemporal lobar degeneration Alzheimer's disease Parkinson's disease and Huntington's disease. These also link to systemic amyloidosis developing in humans with tuberculosis Crohn's disease rheumatoid arthritis and HIV/AIDS. Bioinformatic screens predicted over 250 human proteins contain prion-like domains hypothesized to share transmissible properties. Twenty-nine of known 210 proteins with RNA recognition motifs also have putative prion domains. Aggregation of TDP-43 an RNA-binding protein found in ALS patients promotes misfolding into prion-like conformation. Mutations in genes coding these proteins identified in familial cases promote misfolding. Misfolded TDP-43 forms cytoplasmic inclusions depleted in nucleus. Pathogenic mutations in heterogeneous nuclear riboproteins hnRNPA2B1 and hnRNPA1 exacerbate self-assembly into amyloid fibrils leading to excess accumulation. Aβ plaques and tau tangles characterize Alzheimer's disease where abnormalities initiate pathology by a prion-like mechanism originating within the body. Both multiple system atrophy and Parkinson's disease associate with misfolded alpha-synuclein detected by protein misfolding cyclic amplification.
Common questions
When did the word prion first appear and who coined it?
The word prion first appeared in 1982 when Stanley B. Prusiner coined the term to describe a proteinaceous infectious particle.
What is the molecular mass of normal human prion protein PrPC?
Normal human prion protein PrPC has a molecular mass of approximately thirty-five thousand daltons.
How many years does the incubation period for human prion diseases range from?
Incubation periods for human prion diseases range from five to twenty years or more before symptoms progress rapidly.
Which year did Stanley B. Prusiner receive the Nobel Prize for his work on prions?
Stanley B. Prusiner received the Nobel Prize in Physiology or Medicine in 1997 for discovering that abnormal host proteins convert other proteins into their own shape.
In what year did researchers find plants act as vectors for prions?
Researchers at The University of Texas Health Science Center found plants act as vectors for prions in 2015.