15.3.2: vCJD

 

Ribbon diagram of the 3D structure of PrP^Sc. (Adapted from Fred Cohen Laboratory (UCSF))

Pathogen

• Caused by the  PrP^sc protein, a misfolded form of the normal brain protein  PrP^c
  • PrP^c and PrP^sc have the same amino acid sequence (primary structure); they are just folded in different ways (secondary and teriary structure)
  • Pathogenic form of the protein (PrP^sc ) primarily consists of beta-pleated sheets (Figure \(\PageIndex{1}\)) and is extremely stable, surviving cooking, stomach acid, and disinfectants
• Protein (PrP^c) is normally produced in the brain
• See Prions in Chapter 2 for more information

Figure \(\PageIndex{1}\): Simplified schematic of normal PrP (PrP^C, left) and pathogenic PrP (PrP^Sc, right). Alpha helices are colored yellow and beta-pleated sheets are colored blue("File:PRPCvsPRPSC.jpg" by BQUB13-Hcastillo is licensed under CC BY-SA 3.0)

Habitat

• Normal protein is found in the brains of all mammals
• Misfolded, pathogenic form found in the central nervous system of diseased individuals

Source

• Pathogenic form of the protein is ingested in contaminated meat, most commonly beef from cattle suffering from Bovine Spongiform Encephalopathy (BSE)
  • Deer suffering from Chronic Wasting Disease could also be a source

Epidemiology

• Variant Creutzfeld-Jakob Disease (vCJD) is so called because it affects younger people without a family history, as opposed to sCJD which causes dementia in older people or fCJD which is inherited
• Can take 10 or more years to develop following ingestion of contaminated meat
• Came to public notice after several cases emerged in Britain and became known as "Mad Cow Disease"

Clinical Disease

• A spongiform encephalopathy, a neurodegenerative condition resulting from destruction of brain tissue (Figure \(\PageIndex{2}\))
• Causes brain damage, loss of motor coordination, and dementia.
• Infected individuals are mentally impaired and become unable to move or speak.
• There is no cure, and the disease progresses rapidly, eventually leading to death within a few months or years.

Figure \(\PageIndex{2}\): Creutzfeldt-Jakob disease (CJD) is a fatal disease that causes degeneration of neural tissue. (a) These brain scans compare a normal brain to one with CJD. (b) Compared to a normal brain, the brain tissue of a CJD patient is full of sponge-like lesions, which result from abnormal formations of prion protein. (credit a (right): modification of work by Dr. Laughlin Dawes; credit b (top): modification of work by Suzanne Wakim; credit b (bottom): modification of work by Centers for Disease Control and Prevention)

Primary Virulence Factors

• Protein stability: the PrP^sc protein remains intact through disinfection procedures, cooking, and ingestion.  Once ingested it leaves the digestive tract and eventually localizes in the brain.
• Catalyzes protein misfolding: when PrP^sc interacts with PrP^c it catalyzes the re-folding of the protein to the pathogenic form
• Protein clumping: the PrP^sc proteins clump together (Figure \(\PageIndex{3}\)), similar to amyloid plaques found in Alzheimer's disease, disrupting the neuron function and eventually killing the affected cell.  The released PrP^sc then enters neighboring cells, killing those in turn.  This results in the sponge-like appearance of brains affected by vCJD (Figure \(\PageIndex{2}\))

Figure \(\PageIndex{3}\): Interaction of PrPSc proteins. Left: Three proteins binding (one protein, lower left, is outlined).  Interactions among the hydrophobic beta sheets hold the proteins together.  Right: multiple sets of three proteins stacking to form clumps.  Note the beta sheets on the inside and alpha helices on the outside. (Adapted from "File:Model of a three dimensional structure for PrPSc.jpg" by Kupfer, L; Hinrichs, W; Groschup, M.H. is licensed under CC BY-SA 2.5)

Additional Information:

• Prions, Chapter 2
• https://www.cdc.gov/prions/vcjd/index.html