Prions: Structure, Function and Examples

Table of Content:

• Introduction
• History
• Structure
• Function
• Diseases Caused
• Types of Prions
• Causes of Prion diseases
• Risk Factors for Prion disease
• Symptoms

Introduction:

• Definition: Prion stands for proteinaceous infectious particles.
• Role in Diseases: Prions are infectious agents linked to various mammalian neurodegenerative diseases, such as Creutzfeldt-Jakob disease.
• Mechanism: Diseases occur due to abnormal folding of brain proteins.
• Hypothesis: Prion hypothesis suggests that the infectious agents causing diseases consist solely of proteins.
• Resilience to Ultraviolet Radiation: Prions are resistant to ultraviolet radiation, explaining their resistance. UV radiation breaks down nucleic acids but has limited impact on proteins.
• Denaturation Sensitivity: Prions are receptive to substances denaturing proteins, contributing to their unique characteristics.

Prion Discovery Timeline:

Late 1960s:

• Research indicated that the agent causing sheep Transmissible Spongiform Encephalopathy (TSE) or scrapie was highly resistant to ultraviolet and ionizing radiation.
• These agents, typically vulnerable to radiation, intrigued scientists due to their resistance.

Unclear Nature of Agents:

• Despite resistance, the nature of these particles remained unclear.
• Scientists proposed various possibilities, including proteins, membrane fragments, small DNA viruses, and polysaccharides.

Hypothesis on Nucleic Acid Independence:

• Some researchers suggested that the agent did not depend on nucleic acid for reproduction.

1982 - Stanley B. Prusiner's Contribution:

• Stanley B. Prusiner from the University of California, San Francisco, published an article in Science in 1982.
• Described the process of purifying the scrapie-causing agent.
• Identified it as a protein and introduced the term "prion."

Term "Prion" Coined:

• Prusiner proposed "prion" to denote a small proteinaceous infectious particle.
• Highlighted its resistance to inactivation by procedures modifying nucleic acids.

Recognition and Nobel Prize:

• Prusiner's groundbreaking discovery led to his recognition and the award of the Nobel Prize in 1997.

Prion Structure:

• Prions are present throughout the body, but disease-causing prions exhibit distinct structural characteristics.
• Some prions show resistance to proteases, enzymes that break down proteins.

Isoforms of Prions:

PrPc (Cellular Prion Protein):

• Found on cell membranes.
• Plays a crucial role in cell signaling and adhesion.
• Ongoing research to uncover additional functions.

PrPsc (Scrapie Prion Protein):

• Disease-causing prion.
• Resistant to proteases.
• Affects the conformation of PrPc, inducing changes.
• Contains more beta sheets compared to alpha helices.
• Forms highly structured amyloid fibers.
• Attracts other free proteins to attach to the ends of these fibers.

Interaction Specifics:

• PrPc and PrPsc binding is selective, relying on similar amino acids.
• Cross-species binding is possible but rare.

Function of Prions:

Normal Cellular Prion Protein (PrPc):

• PrPc is a non-infectious, protective form of the protein.
• Predominantly found on the surface of cells in the central nervous system (CNS) and other bodily tissues.
• The specific role of PrPc is not fully understood, but studies suggest it may play a protective role in cells and aid in responding to oxygen deficiency.

Abnormal Prion Protein (PrPsc):

• The infectious particle is a misfolded form of PrPc, called PrPsc.
• Responsible for progressive neurodegenerative conditions.

Diseases Associated:

• Bovine spongiform encephalopathy (BSE or mad cow disease) in cattle and livestock.
• Creutzfeldt-Jakob disease (CJD) in humans.

Mechanism of Action:

• Prions do not multiply within the host organism but act as templates.
• Induce proteins with normal folding to convert into the abnormal prion form.

Exponential Accumulation:

• Newly formed misfolded proteins serve as templates for the conversion of more normal proteins.
• Leads to an exponential accumulation of prions in CNS tissue.

Formation of Plaques:

• Abnormally folded proteins form plaques in the brain.
• These plaques are believed to cause "entanglement" of neurofibrils and interfere with synapse function.

Diseases Caused by Prions

Nature of Prion Diseases:

• Prions are rare and challenging to transmit.
• Progressive neurodegenerative diseases.
• Lack of cure or treatment, and they develop gradually.

Wide Animal Impact:

• Afflict not only humans but various animals.
• Examples include scrapie in sheep, mad cow disease in cows, chronic wasting disease in deer.

Human Prion Diseases:

• Creutzfeldt-Jakob disease
• Fatal Familial Insomnia
• Kuru disease

Insidious Progression:

• Prions can silently spread in the brain for an extended period without symptoms.
• They begin damaging neurons, and symptoms emerge suddenly.
• Rapid decline in the individual's health.

Fatality and Duration:

• All prion diseases are fatal.
• Varied durations, ranging from a few months to several years.

Unique Characteristics:

• Experimental evidence suggests prions are not typical infectious agents.
• Proposed as "self-replicating proteins."

Types of Prion Diseases:

Prion diseases can be categorized into three types: acquired, sporadic, and genetic.

Acquired Prion Disease:

• Occurs when a person is exposed to the infectious protein.
• Rarely contracted, but examples include kuru disease transmitted through cannibalism in New Guinea.

Genetic Prion Disease:

• Result from genetic transmissions.
• Not necessarily inherited from ancestors but can be caused by mutations in DNA.

Sporadic Prion Disease:

• Cause is not confirmed and is believed to be sporadic.
• Most common form of prion disease to date.

Causes of Prion Diseases

Main Cause of Prion Diseases:

• Prion diseases primarily result from the abnormal folding and clumping of prions in the brain, leading to brain damage.
• Manifestations include memory impairment, personality changes, and movement difficulties.

Nature of Prions:

• Prions are highly dangerous infections.
• Caused by agents already present within the body.
• Typically fatal in nature.

Limited Understanding:

• Despite their severity, much remains unknown about prion diseases.

Risk Factors for Prion Disease:

Genetic Predisposition:

• Individuals with a genetic history related to prion disease are at an increased risk.

Consumption of Infected Meat:

• Eating meat infected by "mad cow disease" raises the risk of prion disease transmission.

Contaminated Medical Procedures:

• Exposure to contaminated medical equipment or contaminated corneas can also be a source of prion disease.

Symptoms of Prion Disease:

• Dementia Development: Progressive cognitive decline leading to dementia.
• Hallucinations: Perceptions of non-existent stimuli, affecting sensory experiences.
• Fatigue: Persistent and profound tiredness or weakness.
• Muscle Stiffening: Rigidity and stiffness in the muscles.
• Confusion: Mental disorientation and lack of clarity.
• Speech Difficulty: Challenges in articulation and communication.