Prion

A prion is a misfolded protein capable of inducing abnormal folding in the normal variants of the same protein, ultimately leading to cellular dysfunction and death. Prions are the causative agents of transmissible spongiform encephalopathies (TSEs), a group of fatal, progressive and transmissible neurodegenerative disorders affecting both humans and animals. These conditions are marked by profound damage to neuronal tissues and have no known effective treatments. Unlike conventional pathogens, prions lack nucleic acids and represent a unique class of infectious agent defined solely by aberrant protein conformation.

Nature and Origin of Prions

The term prion—an abbreviation of proteinaceous infectious particle—was introduced by Stanley B. Prusiner in 1982 to describe infectious proteins capable of self-propagation. Prions arise through several mechanisms: spontaneously through rare misfolding events, via inherited genetic mutations in the prion protein gene, or through exposure to existing infectious prion forms. Once established, the misfolded proteins act as templates that induce further misfolding in normally folded proteins of the same type, generating a chain reaction that leads to the aggregation of abnormal proteins.
These misfolded proteins are typically isoforms of the major prion protein (PrP), a naturally occurring cellular protein located predominantly on the cell surface. While its exact physiological role remains uncertain, PrP is involved in cell–cell communication, intracellular signalling and possibly neuronal maintenance.

Prion Protein Structure and Isoforms

The normal cellular form, PrPᶜ, is a glycosylated protein mainly composed of α-helical structures. It is anchored to the cell membrane by a glycophosphatidylinositol (GPI) anchor and occurs in several topological forms, including surface-bound and transmembrane variants. PrPᶜ binds copper ions with high affinity and may play a role in antioxidative processes, although improper metal binding can impair its function.
PrPᶜ is sensitive to proteolysis and can be removed from the membrane by phospholipase C. Under physiological conditions it is not sedimentable and displays dynamic conformational flexibility typical of intrinsically disordered proteins.
The infectious prion isoform, PrPˢᶜ, differs significantly in structural conformation. It contains a higher proportion of β-sheet structure and is resistant to proteases such as proteinase K. PrPˢᶜ molecules assemble into amyloid fibrils held together by intermolecular β-sheets. These fibrils accumulate in neural tissues, either at the cell membrane or as extracellular plaques, disrupting cellular function and causing progressive neurodegeneration. The ends of amyloid fibrils act as templates that recruit and refold additional PrPᶜ molecules, thereby propagating the infectious process.
Distinct fibrillar conformations give rise to prion strains, which differ in incubation periods, pathological patterns and clinical presentation despite being composed of proteins with identical amino acid sequences. Structural diversity among strains has been confirmed through high-resolution cryo-electron microscopy.
A related designation, PrPʳᵉˢ, refers to protease-resistant PrP isoforms generated either in vivo or in vitro. These forms resemble PrPˢᶜ in resistance to proteolytic digestion but may not necessarily be infectious, depending on their structural properties.

Prion Diseases

Prions cause a variety of TSEs, all characterised by sponge-like degeneration of brain tissue, long incubation periods, progressive neurological decline and inevitable fatality. Examples include:

• Scrapie in sheep.
• Chronic wasting disease in deer and related species.
• Bovine spongiform encephalopathy (BSE), also termed mad cow disease, in cattle.
• Creutzfeldt–Jakob disease (CJD) in humans, including sporadic, familial and variant forms.
• Gerstmann–Sträussler–Scheinker syndrome and fatal familial insomnia in humans.
• Kuru, historically observed in Papua New Guinea.

Although prion transmission most commonly occurs within species, cross-species transmission is possible, albeit rare, and often requires specific structural compatibility between donor and host proteins.
The scope of prion-like diseases has broadened with the discovery that other misfolded proteins, such as α-synuclein in multiple system atrophy (MSA) and the aggregates associated with Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis, share mechanistic similarities with PrP prions. These conditions are sometimes described as prion-like due to their ability to seed misfolding and spread within tissues.

Mechanisms of Pathogenesis

Prion accumulation disrupts neural function through multiple mechanisms:

• Formation of extracellular amyloid plaques.
• Interference with membrane integrity.
• Impairment of synaptic signalling.
• Induction of cellular stress and programmed cell death.
• Failure of proteostatic mechanisms that ordinarily degrade misfolded proteins.

The unusual structural stability of prions makes them resistant to heat, chemical disinfectants and standard sterilisation techniques. This poses significant challenges in medical settings, where contaminated instruments may inadvertently transmit disease.

Related Prion-like Proteins and Physiological Functions

Although the physiological role of PrP remains incompletely characterised, studies using knockout models indicate involvement in neural maintenance. Cleavage of PrP in peripheral nerves, for example, appears to activate myelin repair mechanisms in Schwann cells, whereas the absence of PrP can lead to demyelination.
Other proteins, including MAVS, RIP1 and RIP3, share prion-like properties and participate in regulated cell death pathways, particularly during antiviral responses. Their ability to form amyloid-like filaments is essential for signalling cascades that limit viral spread.
Research has also suggested that PrP may influence long-term memory formation, although evidence remains preliminary and the mechanisms uncertain.

Etymology and Pronunciation

The word “prion” derives from protein and infection and reflects the agent’s self-propagating nature. In Prusiner’s original formulation the term was pronounced “pree-on”, although variations exist, including pronunciations influenced by the unrelated name of prion seabirds.

Structural Insights and Research Methods

High-resolution structural studies have played a crucial role in understanding prion biology. Cryo-electron microscopy has revealed detailed architectures of infectious fibrils from both animal and human tissues, showing how PrP molecules stack into extended β-sheet assemblies. Lower-resolution preparations sometimes display two-dimensional crystalline arrays of prion protein, reflecting ordered aggregation.
In vitro techniques such as protein misfolding cyclic amplification have demonstrated the ability of PrPˢᶜ to convert PrPᶜ into protease-resistant forms outside living cells, providing strong support for the protein-only hypothesis of infectivity.

Broader Significance

Prions exemplify a fundamentally unconventional form of biological transmission. Their discovery has reshaped understanding of infection, heredity and protein chemistry. Prion research has influenced diverse fields, from structural biology and neuroscience to public health and sterilisation protocols. The wider recognition of prion-like mechanisms in neurodegenerative diseases continues to drive investigation into protein misfolding and its implications for cellular physiology.