A prion is an infectious agent composed solely of protein, making it distinct from viruses or bacteria. The term is derived from “proteinaceous infectious particle.” Prions are misfolded versions of a protein naturally present in the body, particularly in the brain. This protein exists in two forms: a normal, harmless version and an abnormal, disease-causing one. The abnormal protein induces normal proteins to change their shape, setting off a chain reaction that leads to severe neurodegenerative diseases.
The Normal Prion Protein
The healthy, correctly folded version of the prion protein is cellular prion protein, or PrP^C. It is found in many tissues but is most abundant on the outer surface of nerve cells in the central nervous system. Anchored to the cell membrane, it likely plays a role in cell signaling. While its functions are still under investigation, research indicates PrP^C has several beneficial roles.
Scientists believe PrP^C is involved in multiple processes, including:
- Contributing to the formation of synapses, the junctions where nerve cells communicate.
- Maintaining the myelin sheath, a protective coating that insulates nerve fibers for rapid signal transmission.
- Helping cells respond to low oxygen levels and protecting neurons from apoptosis (programmed cell death).
- Binding to copper ions, which helps maintain the brain’s metal balance and protect against oxidative stress.
The Prion Conversion Process
The central event in prion disease is the transformation of the normal PrP^C protein into its infectious counterpart, PrP^Sc. This conversion is a physical change, not a chemical one, involving a significant alteration in the protein’s three-dimensional folded shape. The normal PrP^C structure, dominated by flexible coils called alpha-helices, is refolded into dense, flat structures called beta-sheets.
This structural shift makes the PrP^Sc protein stable and resistant to cellular enzymes called proteases, which clear away old proteins. The initial PrP^Sc may arise spontaneously, from a genetic mutation, or by exposure to an external source of prions. Once present, PrP^Sc acts as a template, triggering a self-propagating chain reaction.
A misfolded PrP^Sc protein binds to a normal PrP^C protein and forces it to adopt the misfolded shape. This newly converted protein then becomes infectious, causing an exponential accumulation of the abnormal PrP^Sc form. This mechanism is different from viral or bacterial replication, as it does not involve any genetic material.
How Prions Damage Cells
The prion conversion process is toxic to the central nervous system. Because the misfolded PrP^Sc proteins are resistant to cellular breakdown, they accumulate and clump together into aggregates, or plaques. These plaques build up and disrupt the normal function of neurons, leading to cell death.
The accumulation of these protein clumps can trigger apoptosis, the cell’s self-destruct mechanism. As neurons die, microscopic holes form in the brain tissue, creating a distinctive pattern that is a hallmark of these diseases.
Under a microscope, the affected brain tissue is riddled with small vacuoles, giving it a sponge-like appearance. This pathology is why prion diseases are known as transmissible spongiform encephalopathies (TSEs). The loss of brain tissue leads to the severe neurological symptoms associated with these conditions.
Manifestation in Prion Diseases
The accumulation of misfolded prions and subsequent brain damage gives rise to a group of fatal neurodegenerative disorders. These diseases are categorized by their origin: sporadic (occurring spontaneously), inherited (due to a genetic mutation), or acquired (transmitted from an external source).
Human prion diseases include:
- Creutzfeldt-Jakob Disease (CJD), the most common form, which typically appears sporadically in older adults and causes rapid mental deterioration.
- Gerstmann-Sträussler-Scheinker syndrome (GSS) and Fatal Familial Insomnia, which are inherited genetic disorders.
- Kuru, an acquired disease historically transmitted among the Fore people of Papua New Guinea through ritualistic cannibalism.
- Variant CJD, an acquired form linked to consuming beef from cattle infected with “mad cow disease.”
Several prion diseases also affect animals. Scrapie, which affects sheep and goats, was the first such disease to be identified. Bovine Spongiform Encephalopathy (BSE), or “mad cow disease,” affects cattle and raised public health concerns due to its ability to cross the species barrier to humans. Chronic Wasting Disease (CWD) is a highly contagious prion disease spreading among deer, elk, and moose.