Prions

Prions are infectious protein particles that cause a group of fatal, progressive neurodegenerative diseases known as transmissible spongiform encephalopathies (TSEs) in humans and animals. Unlike bacteria, viruses, fungi, or parasites, prions contain no nucleic acids (DNA or RNA) — they are composed solely of misfolded protein. This makes them unique among all known infectious agents and challenges conventional understanding of how infections propagate.
Prion diseases include disorders such as Creutzfeldt–Jakob disease (CJD) and Kuru in humans, Bovine Spongiform Encephalopathy (BSE or “Mad Cow Disease”) in cattle, and Scrapie in sheep. They are always fatal and currently incurable.

Discovery and scientific background

The existence of prions was first hypothesised by Stanley B. Prusiner in 1982, who coined the term “prion” (from proteinaceous infectious particle). His groundbreaking research demonstrated that certain diseases previously thought to be caused by “slow viruses” were in fact caused by an abnormal form of a naturally occurring protein. For this discovery, Prusiner was awarded the Nobel Prize in Physiology or Medicine in 1997.
Before Prusiner’s work, scientists struggled to explain the infectious nature of diseases like scrapie and Creutzfeldt–Jakob disease, since they resisted methods that destroyed nucleic acids — indicating a non-genetic infectious agent.

Structure and mechanism

Prions are abnormal conformations of a normal protein called PrP (prion protein), which is naturally present in the nervous systems of humans and animals.

• The normal, non-infectious form is called PrPᶜ (cellular prion protein).
• The infectious, disease-causing form is known as PrPˢᶜ (scrapie prion protein).

The key difference lies in the protein’s folding structure:

• PrPᶜ has a normal α-helix–rich structure and performs normal cellular functions, possibly related to signal transmission or cell protection.
• PrPˢᶜ is rich in β-sheets, which makes it resistant to proteases, heat, ultraviolet radiation, and chemical disinfectants.

When PrPˢᶜ comes into contact with PrPᶜ, it induces the normal protein to refold into the abnormal shape, setting off a chain reaction that leads to the accumulation of misfolded proteins in the brain. This accumulation disrupts neural function and causes brain tissue to develop a spongy appearance, hence the term spongiform encephalopathy.

Characteristics of prions

Prions display several unusual properties that distinguish them from all other pathogens:

• No nucleic acid content: They replicate without DNA or RNA, through conformational conversion.
• Extremely resistant: They survive conditions that inactivate most microbes — including boiling, radiation, and chemical sterilisation.
• Long incubation periods: Disease symptoms may take years or decades to appear after infection.
• Species barrier: Transmission between species is inefficient but possible (e.g., from cows to humans via BSE).
• Always fatal: There is no known treatment or recovery once symptoms develop.

Prion diseases in humans

1. Creutzfeldt–Jakob Disease (CJD):
   • The most common human prion disease, typically affecting older adults.
   • Characterised by rapid dementia, muscle stiffness, and loss of coordination.
   • Variants include:
     • Sporadic CJD (sCJD): Occurs spontaneously, accounting for most cases.
     • Familial CJD: Caused by inherited mutations in the PRNP gene.
     • Variant CJD (vCJD): Linked to consumption of BSE-contaminated beef.
     • Iatrogenic CJD: Transmitted via medical procedures such as contaminated surgical instruments or tissue transplants.
2. Kuru:
   • Once found among the Fore people of Papua New Guinea, transmitted through ritualistic cannibalism.
   • Caused tremors, laughter fits, and neurodegeneration; now virtually eradicated.
3. Gerstmann–Sträussler–Scheinker Syndrome (GSS):
   • A rare inherited prion disease involving progressive ataxia and dementia.
4. Fatal Familial Insomnia (FFI):
   • Caused by a mutation in the PRNP gene leading to severe insomnia, autonomic failure, and eventual death.

Prion diseases in animals

• Scrapie: Affects sheep and goats; known for centuries. Infected animals show behavioural changes and compulsive scraping against objects (hence the name).
• Bovine Spongiform Encephalopathy (BSE or Mad Cow Disease): First identified in the UK in 1986; spread through feed containing infected animal remains. Later linked to variant CJD in humans.
• Chronic Wasting Disease (CWD): Occurs in deer, elk, and moose in North America and parts of Europe. It spreads through saliva, faeces, and environmental contamination.
• Transmissible Mink Encephalopathy (TME) and Feline Spongiform Encephalopathy (FSE): Rare prion diseases affecting farmed minks and domestic cats exposed to contaminated feed.

Transmission and infection

Prion transmission can occur through several routes:

• Ingestion: Consuming prion-contaminated meat or tissue (e.g., BSE transmission to humans).
• Iatrogenic: Via contaminated surgical tools, transplants, or growth hormone treatments.
• Inheritance: Genetic mutations in the PRNP gene can predispose individuals to prion diseases.
• Direct contact or environment: In animals, prions can persist in soil or bodily fluids, facilitating environmental spread.

Because of their stability, prions can survive sterilisation procedures, posing challenges for infection control in medical settings.

Symptoms and pathology

Prion diseases primarily affect the central nervous system, leading to:

• Rapidly progressive dementia.
• Loss of coordination and muscle control.
• Tremors, rigidity, and involuntary movements.
• Personality changes, hallucinations, and memory loss.
• Fatal outcome within months to a few years.

Microscopic examination of affected brains reveals:

• Spongiform degeneration (tiny holes in neural tissue).
• Amyloid plaque deposition (accumulation of abnormal protein).
• Gliosis (proliferation of supporting cells as a response to damage).

Diagnosis

Diagnosis of prion diseases is complex and often confirmed post-mortem. However, diagnostic tools include:

• MRI scans: Reveal characteristic brain changes.
• EEG (Electroencephalogram): May show periodic sharp wave complexes in CJD.
• Cerebrospinal fluid (CSF) tests: Detection of 14-3-3 proteins or prion biomarkers.
• Genetic testing: Identifies mutations in the PRNP gene.
• Brain biopsy or autopsy: Definitive confirmation through detection of PrPˢᶜ aggregates.

Treatment and prevention

Currently, no cure or effective therapy exists for prion diseases. Treatment is palliative, focusing on symptom management and supportive care.
Preventive measures include:

• Strict control of animal feed to prevent cross-species contamination.
• Surveillance and culling of infected livestock.
• Decontamination protocols in medical facilities, using sodium hypochlorite or extended autoclaving at high temperatures.
• Genetic counselling for families with hereditary prion mutations.

Global health organisations, such as the World Health Organization (WHO) and the World Organisation for Animal Health (WOAH), enforce monitoring and reporting systems for prion-related diseases.

Scientific and medical significance

Prions have profound implications for molecular biology and neuroscience, as they represent a new paradigm of infection — based purely on protein misfolding rather than genetic material. They also offer insight into other neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s disease, which also involve misfolded proteins and aggregation in the brain.
Research into prions has broadened scientific understanding of protein folding, cellular communication, and disease propagation mechanisms.