Prion Pathology

Prions: Misfolded Proteins that Cause Fatal Neurodegenerative Diseases

• Prions are misfolded proteins that can transmit their misfolded shape to normal variants of the same protein, causing fatal neurodegenerative diseases known as transmissible spongiform encephalopathies (TSEs) in humans and animals.

• Prions may misfold sporadically, due to genetic mutations, or by exposure to an already misfolded protein, and their abnormal structure confers them the ability to cause misfolding of other proteins.

• Prion isoforms of the major prion protein (PrP) are hypothesized as the cause of TSEs, including scrapie in sheep, chronic wasting disease (CWD) in deer, bovine spongiform encephalopathy (BSE) in cattle, and Creutzfeldt–Jakob disease (CJD) in humans, which are always fatal and have no known effective treatment.

• Prions form abnormal aggregates of proteins called amyloids, which accumulate in infected tissue and are associated with tissue damage and cell death, and are also responsible for several other neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.

• Prion replication is subject to epimutation and natural selection just as for other forms of replication, and their structure varies slightly between species.

• Prion aggregates are stable and resistant to denaturation by chemical and physical agents, making disposal and containment of these particles difficult, and the risk of iatrogenic spread through medical instruments a growing concern.

• The normal form of PrP is called PrPC, while the infectious form is called PrPSc, which is resistant to proteases and can convert normal PrPC proteins into the infectious isoform by changing their conformation.

• The physiological function of the prion protein remains poorly understood, but it has been suggested to play roles in cell-cell adhesion, intracellular signaling, long-term memory, stem cell renewal, and innate immunity.

• The mechanism of prion replication has implications for designing drugs, and researchers have discovered that endogenous host cofactor molecules are necessary to form PrPSc molecules with high levels of specific infectivity in vitro.

• Prions cause neurodegenerative disease by aggregating extracellularly within the central nervous system to form plaques known as amyloids, which disrupt the normal tissue structure, leading to brain damage and death.

• The incubation period for prion diseases is relatively long, but once symptoms appear, the disease progresses rapidly, and neurodegenerative symptoms can include convulsions, dementia, ataxia, and behavioural or personality changes.

• Prion diseases are untreatable and fatal, but a vaccine developed in mice may provide insight into providing a vaccine to resist prion infections in humans, and genetically engineered cattle lacking a necessary gene for prion production have been developed, making them theoretically immune to BSE.

• Prions and Neurodegeneration: Transmission, Sterilization, Fungal Prions, and Role in Disease

• Prions are misfolded proteins that can cause neurodegenerative diseases and can be formed spontaneously.

• Prion diseases can arise through three different ways: acquired, familial, or sporadic.

• The primary method of infection in animals is through ingestion, and prions can persist in the environment for years.

• Prions can be transmitted through airborne particles, manure, and urine-derived human menopausal gonadotropin.

• Plants can also be a vector for prions, leading to concerns about widespread transmission.

• Sterilizing prions requires denaturation of the protein, and effective decontamination methods include protein hydrolysis and acid detergents.

• Prion-like domains have been found in other mammalian proteins implicated in neurodegenerative disorders, including ALS, Alzheimer's, and Huntington's disease.

• TDP-43 is a protein with a prion-like domain that is found in many neurodegenerative diseases and is largely directed by its prion-like domain.

• Pathogenic mutations have been identified in the prion-like domains of hnRNPA2B1 and hnRNPA1 in familial cases of muscle, brain, bone, and motor neuron degeneration.

• Prions could potentially be used as a bio-weapon due to their high fatality rates and difficulty in detection and decontamination.

• Scrapie in sheep was the first recorded transmissible spongiform encephalopathy, and kuru in humans was the first to show that it could be transmitted to chimpanzees.

• Prions were first hypothesized to be the cause of transmissible spongiform encephalopathies by Carleton Gajdusek, and the protein-only hypothesis was proposed by Tikvah Alper and John Stanley Griffith.Evolution of the Central Dogma and Discovery of Prions

• Francis Crick proposed the Central Dogma of molecular biology in 1958, stating that information flows in one direction, from DNA to RNA to proteins.

• In 1970, Crick revised the Central Dogma to accommodate Griffith's hypothesis of DNA to protein flow, which contradicted his original theory.

• Reverse transcription, discovered by Howard Temin and David Baltimore in 1970, further challenged the Central Dogma.

• Stanley B. Prusiner discovered the infectious protein, which was named a prion, in 1982 at the University of California, San Francisco.

• The prion was found to be absent in healthy hosts and was therefore initially believed to be the product of a silent gene.

• However, the same protein in a different form was discovered in uninfected individuals, leading to the theory that an abnormal form of a host protein can convert other proteins of the same type into its abnormal form.

• The specific protein that the prion was composed of was named the prion protein (PrP).

• Prusiner won the Nobel Prize in Physiology or Medicine in 1997 for his research into prions.

• The discovery of prions challenged the traditional understanding of infectious agents, as they lack nucleic acids.

• Prions are responsible for several fatal neurodegenerative diseases in humans and animals, including Creutzfeldt-Jakob disease and mad cow disease.

• The study of prions has led to the development of new treatments for neurodegenerative diseases and a greater understanding of protein folding and misfolding.

• The discovery of prions has also contributed to the ongoing evolution of the Central Dogma of molecular biology.