Session 11: Prions & Prion Diseases

Prion disease

A disease caused by an abnormal protein particle that infects brain tissue.

Neurodegenerative disease.

Alternatively known as Transmissable Spongiform Encephalopathy (TSE).

Sheep prion disease

Scrapie

Cow prion disease

Bovine spongiform encephalopathy (BSE) or mad cow disease

Deer prion disease

Chronic wasting disease (CWD)

In humans, prion diseases include...

- Creutzfeldt-Jakob disease (CJD) and v-CJD

- Kuru

- Fatal familial insomnia (FFI)

- Gerstmann-Straussler-Scheinke syndrome (GSS)

Symptoms of prion disease

Anxiety/depression

Ataxia

Memory loss, loss of cognition

Dystonia

Incontinence (bowl & urinary)

Inevitably fatal (no cures, only symptomatic treatment)

Characteristics of prion disease

- Neurodegenerative

- Neuronal death leading to spongiform appearance of brain

- Proliferation of astrocytes & microglia

- Build up of amyloid plaques (protein aggregates)

- Evidence of oxidative stress

Prion diseases can occur via three mechanisms

1) Sporadic (spontaneous) = 85-90%

2) Genetic (familial) = 10-15%

3) Acquired (infectious/transmitted) = 2-5%

Different forms of prion disease affect different parts of the brain

Prion disease of the cerebral cortex causes what prion disease?

Classical CJD

Different forms of prion disease affect different parts of the brain

Prion disease of the thalamus causes what prion disease?

Fatal Familial Insomnia

Different forms of prion disease affect different parts of the brain

Prion disease of the brainstem causes what prion disease?

Scrapie

BSE

Chronic wasting disease (CWD)

Different forms of prion disease affect different parts of the brain

Prion disease of the cerebellum causes what prion disease?

Kuru

Histology of prion diseases

Characteristic prion pathology

- Spongiform changes

- Microglia

Amyloid plaques

Comprised of protein

B-pleated sheet rich

Proteins stack up to make fibrils (fibres)

Clump together to make a plaque

Prion protein (PrP)

Prion fibrils

Protein found in prion diseases (TSEs)

Prion proteins

Protein found in Alzheimer's disease

Amyloid-beta protein

Protein found in Parkinson's disease

Alpha-synuclein

Protein found in Huntington's disease

Huntingtin

Protein found in Wilson's disease

Defects in copper metabolism

Protein found in ALS

Defects in superoxide dismutase

Which prion diseases are transmissible?

- Kuru

- BSE

- v-CJD

Evidence that prion diseases are transmissible

- Injections of diseased brain tissue into another healthy animal of same species transmits the disease

- Suggests an infectious agent such as a virus BUT no viral evidence has been found in brain extracts

- Treating the brain extracts with agents (e.g., ultraviolet light/nucleases) that destroy nucleic acids does NOT reduce their infectiousness

- This evidence indicates that the infectious agent in the TSEs is a protein

Routes of infection of prion disease

Ingestion (kuru, v-CJD)

Iatrogenic

Corneal grafts

Dura mater grafts

Human derived growth injection hGH

Experimental transmission in animal models

Describe pathogenesis of prion disease

1) Prions detected by immune system (resistant to proteolysis)

2) Prions replicate inside lymphoid tissue (especially follicular dendritic cells) e.g., tonsils, spleen, peyer's patches, lymph nodes

3) Prions enter the CNS via nerves of the autonomic nervous system (ANS)

Key event in prion disease pathogenesis

Seroconversion of PrPc (normal cellular form of prion protein) to PrPSc

Some features of normal cellular form of prion protein (PrPc)

GPI anchored (plasma membrane)

Monomeric

Protease sensitive

Binds copper

Alpha helices present

Synaptic location

Some features of diseased form of prion protein (PrPSc)

Extracellular

Aggregated

Protease resistant

No specific copper bound

High beta sheet content

Associated with infectivity

Not easily decontaminated

Conformations of PrP

Proposed mechanisms of PrPSc catalysed conversion

1) Template directed refolding model

2) Nucleation dependent polymerisation model (seeding)

Mechanism of neurodegeneration in prion disease

1) PrPSc is cytotoxic - it accumulates in cells causing damage to neurons

2) Excess prion accumulation leads to neurodegeneration

3) MFGE8 secreted by astrocytes - promotes the phagocytosis of apoptotic neurons

4) Microglia clear apoptotic neurons

How do inherited prion diseases come about?

Mutations destabilise PrPc and make PrPSc more energetically favourable

CJD can occur with no family history of the disease and no known exposure to infectious prions & late-onset.

How do sporadic prion diseases come about?

- A spontaneous somatic mutation may have occurred in one of the prnp genes in a cell

- Normal PrPC protein may have spontaneously converted into the PrPSc form

- Tends to be a susceptibility polymorphism in their prnp genes

Guidance when treating patients with prion disease

- 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, i.e., liquid repellent operating gown, over a plastic apron, gloves, mask and goggles, or full-face visor; for symptomatic patients – this protective clothing should be single-use

- Single-use disposable surgical instruments and equipment used wherever possible – subsequently destroy with incineration or sent to instrument store

- Effective tracking of reusable instruments should be in place, so that instruments can be related to use on a particular patient

Blood & blood product guidance (safety)

Safety measures to reduce any possible risk of spreading v-CJD through blood…

- Withdrawal & recall of any blood components donated by anyone who develops v-CJD & importing plasma from USA

- Removing white blood cells from all blood used for transfusions (leucodepletion)

- Not accepting donations from people who may have received blood transfusion since 1980

- Promote appropriate use of blood, tissues and alternative through NHS

Potential pharmaceutical interventions for prion disease

- Prnp knockdown

- Antibodies prevent prion conversion

- Antibodies prevent prion aggregation

- Compounds interfere with neurotoxicity