Lecture 11.1: Prions Flashcards
What are Prions?
Prions are mis-folded proteins with the ability to transmit their mis-folded shape onto normal variants of the same protein
What are Prion Diseases?
- Neurodegenerative diseases
* Alternatively known as Transmissible Spongiform Encephalopathy (TSE)
What are some Examples of Prion Diseases? (4)
- Creutzfeldt-Jakob disease (CJD) & variant Creutzfeldt-Jakob disease (vCJD)
- Kuru
- Fatal Familial Insomnia (FFI)
- Gerstmann-Straussler-Scheinke syndrome (GSS)
What are Symptoms of Prion Diseases? (6)
- Anxiety & Depression
- Ataxia (loss of physical coordination)
- Memory Loss
- Loss of Cognition
- Dystonia (muscle spasms)
- Incontinence (bowel & urinary)
Why are Prion Diseases so dangerous?
• Inevitably fatal: no cures, only treatments to ease symptoms
• Most people with CJD will die within a year of the symptoms starting (often from
infection)
What are Physiological Characteristics of Prion Diseases?
- Neuronal death leading to a spongiform appearance of the brain
- Proliferation of astrocytes & microglia
- Build up of amyloid plaques (protein aggregates)
- Evidence of oxidative stress
Are Prion Diseases common?
No, they are very rare
What are the 3 Mechanisms by which Prion Diseases occur?
- Sporadic (spontaneous)
- Genetic (familial)
- Acquired (infectious/ transmitted)
Sporadic (Spontaneous) occurrence of Prion Diseases
- 85-90% of cases
- Symptoms usually develop between the ages of 60 and 65
- 1 -2 deaths per million people, 127 deaths in 2019
Genetic (Familial) occurrence of Prion Diseases
- 10-15% of cases
- Symptoms usually develop in early 50s
- 1 per 9 million people, 5 deaths in 2019
Acquired (Infectious/Transmitted) occurrence of Prion Diseases
- 2-5% of cases
- V. rare
- 1 death from iatrogenic infection in 2019
What part of the Brain is affected in Classic CJD?
Cerebral Cortex
What is the function of the Cerebral Cortex in the Brain?
Responsible for the higher-level processes of the human brain, including language, memory, reasoning, thought, learning, decision-making, emotion, intelligence and personality
What part of the Brain is affected in Fatal Familial Insomnia?
Thalamus
What is the function of the Thalamus in the Brain?
• Your thalamus is your body’s information relay station
• All information from your body’s senses (except smell) must be processed
through your thalamus before being sent to your brain’s cerebral cortex for
interpretation
What part of the Brain is affected in Kuru?
Cerebellum
What is the function of the Cerebellum in the Brain?
Important for making postural adjustments in order to maintain balance
What Prion Diseases affect the Brain Stem?
- Scrapie
- BSE
- Chronic Wasting Disease
What is the function of the Brain Stem in the Brain?
The brain stem is responsible for regulating most of the body’s automatic functions that are essential for life (regulation of heart rate, breathing, sleeping, and eating)
Amyloid Plaques Structure
- Comprised of protein
- β-sheet rich
- Proteins stack up to make fibrils (fibres)
- Clump together to make a plaque
- Prion protein (PrP)
Routes of Infection for Prions
- Ingestion
* Iatrogenic (relating to illness caused by medical examination or treatment)
Types of Iatrogenic Infection for Prions
- Corneal Grafts
- Dura Mater Grafts
- Human derived Growth Hormone Injection (hGH)
- Experimental transmission in animal models
How do Prions move from Mouth to Brain?
- Prions detected by immune system
- Resistant to proteolysis
- Replicate in lymphoid tissue (especially follicular dendritic cells)
- Enter central nervous system by nerves of the autonomic nervous system
What is PrPC?
There is a normal cellular form of the prion protein PrPC
PrPC vs PrPSc
- PrPC & PrPSc share the same amino acid sequence
- Coded by prnp gene on xsome 20 (human)
- PrPC to PrPSc conversion is a key event in disease
PrPC Structure & Characteristics (8)
- GPI Anchored (Plasma Membrane)
- Monomeric
- Protease Sensitive
- Binds Copper
- Synaptic Location
- 3 α–helices
- 2 β-strands
- NMR & X-ray
PrPSc Structure & Characteristics (7)
- Extracellular and Aggregated
- Protease Resistant
- No specific copper bound
- Associated with Infectivity
- Not easily Decontaminated
- Secondary Structure
- β-strand rich
Mechanism of Neurodegeneration via Prions (4 Steps)
- PrPSc is cytotoxic
- Potential loss of antioxidant activity of PrPC
- Apoptotic neurones cleared by microglia
- Leave ‘gaps’ (sponge like) and protein plaques
What causes initial formation of PrPSc in Sporadic Prion Diseases?
- Definitive cause is uncertain
- A spontaneous somatic mutation may have occurred in 1 of the Prnp genes
- Normal PrPC protein may have spontaneously converted into the PrPSc form
- Tends to be a susceptibility polymorphism in their Prnp genes
Precautions for patients with/“at increased risk” of CJD undergoing Surgery (7)
• Perform the intervention in an operating theatre
• Schedule at the end of the list, to allow cleaning
• Involve the minimum number of personnel required
• Protective clothing should be worn (single use if possible)
• Single-use disposable surgical instruments and equipment should be used
where possible
• Equipment subsequently destroyed by incineration or sent to the instrument
store
• Effective tracking of reusable instruments should be in place, so that
instruments can be related to use on a particular patient
Safety Measures to reduce any possible risk of spreading vCJD through Blood (5)
• Withdrawal of any blood components donated by anyone who develops vCJD
• Removing WBC from all blood used for transfusions (leucodepletion)
• Not accepting donations from people who may have received a blood
transfusion since 1980
• Promoting the appropriate use of blood, tissues & alternatives in the NHS
• Led to a reduced amount of blood transfused during and following surgery
Potential Pharmaceutical Interventions for Prion Diseases (4)
1) Pnrp knockdown (reduces PrPC production)
2) Antibodies prevent prion conversion (PrPC to PrPSc conversion restricted)
3) Antibodies prevent prion aggregation (PrPSc aggregate formation prevented)
4) Compounds interfere with neurotoxicity (PrPC-mediated PrPSc toxicity)
