Introduction

Cruetzfeldt-Jakob Disease (CJD) is a rare and fatal neurodegenerative disease that causes changes to the brain tissue leading to brain damage. Many of the symptoms are associated with dementia; memory loss, coordination issues and behavioural changes. CJD results from proteins in the brain called prions, which abnormally change shape by folding to cause dysfunction. There are different types of prion disease, one resulting in the well-known “mad-cow disease” outbreak. The mechanisms of prion folding have been elusive to experts but have been continually researched due to their poor prognosis. Understanding the role of these prions will be crucial for research into disease pathology and hopefully aid in discovering a cure.

Creutzfeldt-jakob disease

Symptoms

Symptoms of CJD vary based on several factors, including the type and stage of disease and age of onset. Some of the most commonly noted symptoms include:

• Confusion
• Memory problems
• Behavioural problems: agitation, irritability, aggression
• Personality changes 
• Mobility issues: muscle weakness and/or balance
• Slurred speech
• Depression/anxiety
• Insomnia

These will worsen as the disease progresses, eventually resulting in muscle spasms, extreme memory loss, and speech loss. Towards the end stages of the disease, patients will become completely bedridden, and will eventually become fatal.¹

The role of prions 

Prions, short for proteinaceous infectious particles, are proteins with the ability to become infectious. They are made of amino acids that join together to produce long chains, folded into proteins. The differential folding and shape that proteins produce are essential for their function.

Normal structure and functions

Prion proteins, often referred to as PrPc, are present in human cells at the cell membrane, most abundantly at the surface of neurons in the brain. Their normal functionality is not entirely understood but is thought to be associated with neuronal communication.² 

The normal prion protein consists of a high alpha-helix content and low beta-sheet content. 

Alpha-helices 

An alpha-helix describes the coil-like shape of amino acids shaped by hydrogen bonding. This formation is sometimes used to ensure certain amino acids can’t be interacted with, as they are tucked away in the inside of the helix, while others are presented outwards to be available for bonding. 

Beta-sheets

Beta-sheets consist of a long amino acid chain or “sheet” which is also held together by hydrogen bonds, but by a different arrangement of amino acids compared to alpha helices. This formation has a different function, as it can remain flat, allowing space for other amino acid groups to fit around it.³

Abnormal structures and function

When abnormal folding occurs, most alpha helices change to beta sheets in the prions. This creates the PrPsc protein, the abnormal protein, with beta-strand content increasing from 3% to 43%.⁴ Prions now obtain a flat, straight structure which will recruit additional prions to misfold and clump together.⁵

With their new conformation, the abnormal beta-stranded prions can stack themselves closer together, increasing interactions between each other and nearby molecules. These aggregated proteins clump together, causing plaques in the brain and central nervous system.

Mechanisms of neurodegeneration

The mechanisms by which PrPsc proteins lead to degeneration are still largely unknown, although current research has presented some hypotheses which include: 

• Protein misfolding 
• Impaired degradation
• Triggering the inflammatory response 

Protein mis-folding

The process of increased PrPsc results in plaque build up amongst the neurons, blocking essential neuronal messaging pathways.⁶ It is suggested that this causes direct toxicity to neurons.⁷

Regardless of how prions affect the pathways in the brain, the result remains the same - neuronal cell death.

Impaired degradation

Misfolded prions are more resistant to degradation within the gastrointestinal tract due to their new conformation, becoming insoluble in the acidic environment of the gut.⁸ 

Subsequently, they can move throughout the bloodstream to reside in the brain. This is most apparent in variant CJD, a subtype of CJD that can be transmitted through contaminated food products.

Inflammatory response

Evidence of increased microglia activity has been found in models of prion disease.⁹ These are immune cells localised to the brain, triggered to fight off infections. If the immune response is great enough, the chronic activation can go into overdrive, resulting in the degeneration of neurons and neurotoxicity.¹⁰ In short, the body starts attacking itself.

Forms of CJD

There are 4 forms of Creurzfeldt-Jakob disease, each with different causes and characteristics.

Sporadic CJD

Sporadic CJD is the most common form of the disease, and as the name suggests, seems to be randomly occurring. 

The incidence is very rare, with only 1-2 new cases per 1 million people per year, and typically affects older adults and progresses rapidly¹¹ 

Hereditary CJD

Hereditary or genetic/familial CJD describes a rare genetic disorder where a person can inherit a mutation from a parent that predisposes them to CJD.

The gene that codes for CJD is the human PrP gene (PRNP) and a total of 50 different mutations have been identified to cause CJD.¹² 

It is an autosomal-dominant inheritance mutation, which means that one person has the mutation, their child would have a 50% chance of developing the disease. An individual with these types of mutations will not necessarily suffer from CJD, but they are at a predisposition for increased prion folding – their risk of obtaining CJD is greater.

The age for symptom development can vary depending on what type of mutation a person carries, but genetic CJD usually occurs earlier in life than sporadic. However, progression takes longer, over a year or more.¹³ 

Iatrogenic CJD

This type of CJD describes those transferred from infected individuals after surgeries or medical examinations, including corneal transplants or unsterile equipment used on the brain. Standard sterilisation techniques are not adequate against prions, as they differ biologically from bacteria and viruses.

Since the discovery of iatrogenic transmission, procedures have been initiaited to eradicate contamination. This includes the destruction of any instruments used by medical professionals and rigorous genetic testing to confirm/deny CJD presence. 

Variant CJD  

Bovine spongiform encephalopathy (BSE) or “mad cow disease” is a prion disease in cattle, which can be transmitted to humans when consumed. It shows similar symptoms in cattle as CJD does in humans – behavioural changes, mobility issues and weight loss.

The process of mad cow disease is very similar to CJD. The misfolded aggregated prion proteins are present within the cow which can be present in the beef produced after death. Once consumed, the aggregate infectious prions can travel through the blood towards the brain. They can insert into the membrane of cells and disrupt natural processes to cause cell death. This causes changes in behaviour, memory loss, and inevitably results in death according to the National Institute of Neurological Disorders and Stroke. 

Transmission isn’t always guaranteed, as an infected cow may not always transmit to humans. This is because when consuming beef, we do not eat parts that are high in prions such as the brain, therefore it is possible to not get this disease even though you’ve consumed an infected cow.

Luckily, government regulation and strict instructions for bovine health have essentially eliminated the chance of contracting CJD in this way. For example, animal carcasses infected with BSE by law must be destroyed appropriately according to the Scottish Government website. Other developing countries however may not hold the same regulations, so the risk worldwide still prevails.

Diagnosis

Diagnosis usually involves ruling out other diseases first as brain biopsy is the only guaranteed way to assess CJD.

Diagnostic tests

Treatment

Currently, there are no treatment options for any of the types of Creutzfeldt-Jakob Disease. It is fatal in 100% of cases.Unlike other diseases, it is characterised genetic mutation causing changes within the body's own cells, instead of bacterial or viral infections which can be fought off through medications. The only treatment involves pain management therapies, symptom reduction and hospice care to keep patients as comfortable as possible.

Summary

The mechanism of CJD is complex and differs from patient to patient, with rapid progression in all cases. Despite  no cure, preventative measureshave been established by local governments and health bodies to ensure transmission of this fatal disease is as low as possible. Additionally, for the inherited type of disease, there are genetic tests families can take to find out their chance of giving the mutation to their children, lowering the incidence of the disease. As more information is discovered about prions and their role in disease, research continues in the hope of one day finding a cure for this perplexing disease.