Creutzfeld-Jakob's Disease Research

Creutzfeldt-Jakob’s Disease (CJD)

Brady Douglas

Neurodegenerative disorder that leads to complete loss of brain function and ultimately death

- Caused by infectious agents called prions.- A prion is an abnormally folded protein that promotes the misfolding of it’s native counterparts- Prions are resistant to proteases

CJD is just one of many different types of Transmissible Spongiform Encephalopathies caused by prion proteins

History of CJD• 1920s: CJD condition first described by German

neurologists Hans Gerhard Creutzfeldt and Alfons Maria Jakob– It became infamously known as a rare form of dementia that

was incurable and universally fatal• 1980s: BSE epidemic in the UK (> 1 million cows)

http://news.discovery.com/animals/mad-cow-disease-causes-cattle-eyes-to-glow.html

History of CJD• 1983: Famous Choreographer George Blanchine

dies of CJD• 1994: first case of BSE in humans (link was first

established)• 1996: New disease related to BSE was first

reported, defined as a “new variant” of CJD (vCJD)

• Today: Since the first case of vCJD, the following cases have been reported: 163 cases in the United Kingdom, 23 in France, 4 in Ireland, 3 in the United States, 3 in Spain, 2 in the Netherlands, 2 in Portugal, 1 in Italy, 1 in Canada, 1 in Saudi Arabia and 1 in Japan.

Genetic Component

• Familial forms of CJD can be acquired by inherited mutations to the PRNP gene.

• 10-15% of CJD cases are inherited• Mode of inheritance: Autosomal Dominant

(one mutated copy of the gene is sufficient to acquire this disease, can be inherited from a single parent)

• Infected individual has a family history of CJD and/or tests positive for the mutated gene.

Other Forms of CJD

• Sporadic/Idiopathic (85% of cases)– Disease arises spontaneously, unsure of it’s origin– Usually appears later in life (between 50 to 75)

and kills 90% of patients within a year– Patients had no known risk factors– 1/1,000,000 people affected annually worldwide– Approximately 200 are at risk every year in the

USA– Possible cause: random mutation of the PRNP

gene

Other Forms of CJD

• Iatrogenic (vCJD)– Rarest form, affecting less than 1% of patients– Common in younger patients ( > 40 years old)– Can be acquired through various routes

Ingestion of meat products contaminated with BSE Blood transmission from an affected individual Use of plasma derived medications from an affected individual• Exposure to infected brain tissue or spinal cord fluid through

medical procedures, i.e., dura mater grafts, corneal transplants, skin transplants, or the implantation of tainted stereotactic electrodes or surgical instruments.

Genetic Location of the Prion Protein

• Cytogenetic location: 20p13 • Genomic coordinates

(GRCh37): 20:4,666,796 - 4,682,233

• From NCBI (http://omim.org/entry/176640)

(http://fr.wikipedia.org/wiki/Chromosome_20_humain)

Phenotypic Manifestation• 4 basic physiological characteristics (shared by all TSEs)

– Spongiform appearance of brain tissue; many tiny holes` visible by the naked eye.

– Neuronal Loss.– Astrocytosis- unusually large amount of astrocytes in the

brain tissue due to the destruction of nearby neurons.– Amyloid plaques formed by aggregates of the prion protein.

http://www.humenhealth.com/creutzfeldt-jakob-disease-cjd

• The normal prion protein is water soluble and is dominated by alpha helices. It resides in the plasma membranes of lymphocytes (transmissible by blood)

• The diseased prion is water insoluble and is dominated by beta sheets. This conformation favors the formation of the detrimental protein aggregates that lead to chronic dementia and death

• http://www.riversideonline.com/health_reference/Infectious-Disease/DS00531.cfm

• http://www.cdc.gov/ncidod/dvrd/cjd/classic_cjd_tissue_slide_large_view.htm

Symptoms

– Headaches– Anxiety– Insomnia– Depression– Behavioral changes– Agitation– Confusion

– Memory loss– Impaired Judgment– Lack of Muscle

Coordination– Speech and visual

problems

The disease process can be broken down into 3 clinical phases:

First stage: Subtle symptoms, often overlooked as other problems

Symptoms

– Spasticity – Rigidity– Myoclonic jerks– Limb weakness

The disease process can be broken down into 3 clinical phases:

Second stage: Rapid mental deterioration, severe dementia state within 6 months

Symptoms

– Completely bedridden– Blind – Mute– Glazed, vacant stares– Myoclonic seizures

– Increased susceptibility

to heart/respiratory failure, pneumonia and other infections

– Most lapse into a coma before death

The disease process can be broken down into 3 clinical phases:

Third stage: Terminal stage

How to detect/cure this disease?

• CJD is still an incurable disease as of today• No single confirmatory test as of today, can

only rule out other forms of dementia and curable encephalopathies.

• Only true way to confirm CJD pre-mortem is a biopsy of the brain tissue, but by this time, dementia has already progressed well into the second stage.

Approaches to Treatment

• Find and isolate agents that reduce PRPN expression, or that destabilize the mature form– Congo red

• Gene Therapy– In most species, genes encoding protease resistant

products are considered to be errors and are inhibited by the natural machinery

– Could it be possible to incorporate these genes into our genome?

– Must continue to increase our knowledge

Current Research Shows Infectious Prions Can Arise Spontaneously in Normal Brain Tissue

• Recent new study (2010) shows that spontaneous appearances of prions in healthy brain tissue can be promoted by contact with steel surfaces.

• Participants: Scripps Research Institute in Florida and the University College London (UCL) Institute of Neurology in England

Citations Cyngiser, Tracy A. "Creutzfeldt-Jakob Disease: A Disease Overview." American

Journal of Electroneruodiagnostic Technology 48 (2008): 199-208.Heath, C. A., Cooper, S.A., Murray, K., Lowman, A., Henry, C., MacLeod,

M.A., ...Will, R.G. (2010). Validation of diagnostic criteria for variant Creutzfeldt-Jakob disease. Annals of Neurology, 67(6), 761-770.

Kelechi, Robert, and Ferdinand C. Nwanebu. "Prion and Prion Diseases." African Journal of Clinical and Experimental Microbiology 8.2 (2007): 38-52.

Liras, Antonio. "The Variant Creutzfeldt-Jakob Disease: Risk, Uncertainty or Safety in the Use of Blood and Blood Derivatives?" (2008). International Archives of Medicine. Web. <http://www.intarchmed.com/content/1/1/9>.

Manuelidis, Laura, Ying Liu, and Brian Mullins. "Strain-specific Viral Properties of Variant Creutzfeldt-Jakob Disease (vCJD) Are Encoded by the Agent and Not by Host Prion Protein." J Cell Biochem. 106.2 (2009): 220-31. NIH Public Access. Web.

"News Release." The Scripps Research Institute. UK Medical Research Council, 26 July 2010. Web. 26 Sept. 2011. <http://www.scripps.edu/news/press/20100726.html>.