Lecture 11.1: Prions

Question 1

What are Prions?

Answer 1

Prions are mis-folded proteins with the ability to transmit their mis-folded shape onto normal variants of the same protein

Question 2

What are Prion Diseases?

Answer 2

• Neurodegenerative diseases

* Alternatively known as Transmissible Spongiform Encephalopathy (TSE)

Question 3

What are some Examples of Prion Diseases? (4)

Answer 3

• Creutzfeldt-Jakob disease (CJD) & variant Creutzfeldt-Jakob disease (vCJD)
• Kuru
• Fatal Familial Insomnia (FFI)
• Gerstmann-Straussler-Scheinke syndrome (GSS)

Question 4

What are Symptoms of Prion Diseases? (6)

Answer 4

• Anxiety & Depression
• Ataxia (loss of physical coordination)
• Memory Loss
• Loss of Cognition
• Dystonia (muscle spasms)
• Incontinence (bowel & urinary)

Question 5

Why are Prion Diseases so dangerous?

Answer 5

• 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)

Question 6

What are Physiological Characteristics of Prion Diseases?

Answer 6

• 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

Question 7

Are Prion Diseases common?

Answer 7

No, they are very rare

Question 8

What are the 3 Mechanisms by which Prion Diseases occur?

Answer 8

• Sporadic (spontaneous)
• Genetic (familial)
• Acquired (infectious/ transmitted)

Question 9

Sporadic (Spontaneous) occurrence of Prion Diseases

Answer 9

• 85-90% of cases
• Symptoms usually develop between the ages of 60 and 65
• 1 -2 deaths per million people, 127 deaths in 2019

Question 10

Genetic (Familial) occurrence of Prion Diseases

Answer 10

• 10-15% of cases
• Symptoms usually develop in early 50s
• 1 per 9 million people, 5 deaths in 2019

Question 11

Acquired (Infectious/Transmitted) occurrence of Prion Diseases

Answer 11

• 2-5% of cases
• V. rare
• 1 death from iatrogenic infection in 2019

Question 12

What part of the Brain is affected in Classic CJD?

Answer 12

Cerebral Cortex

Question 13

What is the function of the Cerebral Cortex in the Brain?

Answer 13

Responsible for the higher-level processes of the human brain, including language, memory, reasoning, thought, learning, decision-making, emotion, intelligence and personality

Question 14

What part of the Brain is affected in Fatal Familial Insomnia?

Answer 14

Thalamus

Question 15

What is the function of the Thalamus in the Brain?

Answer 15

• 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

Question 16

What part of the Brain is affected in Kuru?

Answer 16

Cerebellum

Question 17

What is the function of the Cerebellum in the Brain?

Answer 17

Important for making postural adjustments in order to maintain balance

Question 18

What Prion Diseases affect the Brain Stem?

Answer 18

• Scrapie
• BSE
• Chronic Wasting Disease

Question 19

What is the function of the Brain Stem in the Brain?

Answer 19

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)

Question 20

Amyloid Plaques Structure

Answer 20

• Comprised of protein
• β-sheet rich
• Proteins stack up to make fibrils (fibres)
• Clump together to make a plaque
• Prion protein (PrP)

Question 21

Routes of Infection for Prions

Answer 21

• Ingestion

* Iatrogenic (relating to illness caused by medical examination or treatment)

Question 22

Types of Iatrogenic Infection for Prions

Answer 22

• Corneal Grafts
• Dura Mater Grafts
• Human derived Growth Hormone Injection (hGH)
• Experimental transmission in animal models

Question 23

How do Prions move from Mouth to Brain?

Answer 23

• 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

Question 24

What is PrPC?

Answer 24

There is a normal cellular form of the prion protein PrPC

Question 25

PrPC vs PrPSc

Answer 25

* 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

Question 26

PrPC Structure & Characteristics (8)

Answer 26

* GPI Anchored (Plasma Membrane) * Monomeric * Protease Sensitive * Binds Copper * Synaptic Location * 3 α–helices * 2 β-strands * NMR & X-ray

Question 27

PrPSc Structure & Characteristics (7)

Answer 27

* Extracellular and Aggregated * Protease Resistant * No specific copper bound * Associated with Infectivity * Not easily Decontaminated * Secondary Structure * β-strand rich

Question 28

Mechanism of Neurodegeneration via Prions (4 Steps)

Answer 28

* PrPSc is cytotoxic * Potential loss of antioxidant activity of PrPC * Apoptotic neurones cleared by microglia * Leave ‘gaps’ (sponge like) and protein plaques

Question 29

What causes initial formation of PrPSc in Sporadic Prion Diseases?

Answer 29

* 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

Question 30

Precautions for patients with/“at increased risk” of CJD undergoing Surgery (7)

Answer 30

• 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

Question 31

Safety Measures to reduce any possible risk of spreading vCJD through Blood (5)

Answer 31

• 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

Question 32

Potential Pharmaceutical Interventions for Prion Diseases (4)

Answer 32

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)