Prion - Replication, Isolation, Pathogenesis

Replication of Prion

Prions do not contain any nucleic acid but have normal prion protein known as prion protein cellular PrP^C. PrP^C has a significant amount of helical configuration. In its α-helical configuration, PrP^C is sensitive to degradation by the protease enzyme.

But when PrP^C reconfiguration into the β-sheet configuration, known as prion protein scrapie (PrP^C), disease occurs. They are resistant to degradation by protease and resistant to radiation, heat, and disinfectants such as formaldehyde.

They then aggregate into filaments that disrupt neuron functions and cause the death of cells. Two forms i.e. both normal α-helical configuration and abnormal β-sheet form have the same amino acid sequence but differ in their configuration

The newly formed prions can then go and convert more proteins themselves. This triggers a chain reaction that produces large amounts of prion form known as replication of prion. Because of their abnormal shape, PrP^C sticks together. Over time these molecules stack up to form long chains called “amyloid fibers.”

Culture/Isolation of Prion

Prions cannot be culture/isolated in tissues or isolated in any experimental models.

Pathogenesis of Prion

Prions disease is transmitted either orally or transcutaneously. But how prions reach their target i.e. CNS is yet to be fully understood. It is suggested that prions may reach the CNS via:

• splanchnic nerves of the thoracic spinal cord

• parasympathetic fibers connecting with the brain

• blood

PrP^C is found in most tissue of the host but is expressed in higher quantities in CNS particularly the neurons- the main site of action of prions.

Steps:

1. PrP^C binds to the PrP^C of the host

2. PrP^C is ingested by neurons and phagocytic cells but cannot be degraded and remains intact

   (formation of vacuoles)

3. It causes vacuolation of the neuron (a key pathological change in encephalitis)

4. In addition, prions accumulative in high concentration forming amyloid fibrils/fibers which causes brain tissue damage

5. Proliferation and hypertrophy of astrocytes; and fusion of neurons and adjacent glial cells also occurs

(In the asymptomatic patients, a protein called 14-3-3 brain protein has been detected in CSF)