Introduction to Prions

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Prions

What Are They?
Prions are proteinaceous transmissible pathogens, and are believed to infect and propagate the conformational changes of the native proteins into the the abnormally structured form.

They are often called Spongiform Encephalopathies due to the swelling of the brain, accompanied with the observation of vacuoles like structures.

Different prions affect different regions of the brain
• Cerebral cortex: the symptoms include loss of memory and mental acuity, also visual imparement (CJD). • Thalamus: Fatal Familial Insomnia (FFI).

• Cerebellum: lose the control of body movements and difficulties to walk (kuru, GSS). • Brain stem: In the mad cow disease (BSE), the brain stem is affected.

3

Formation Of A Prion (in the cell) α-helix β-sheet Conformational change PrPSc Normal protein (folded structure) PrPC Aggregation Gain of toxic activity Loss of biological function

Disease-associated protein (misfolded structure)

PrPC
The normal protein is called PrPC (for cellular) is a transmembrane glycoprotein (neurons, lymphocytes); its function is unknown; it binds Cu2+ (regulation its homeostasis)

PrPSc
The abnormal, disease-producing protein is called PrPSc (for scrapie) has the same amino acid sequence (primary structure)

is monomeric and easily digested by proteases

is multimeric and resistant to digestion by proteases

When PrPSc comes in contact with PrPC, it converts the PrPC into more of itself These molecules bind to each other forming aggregates

PrPC and PrPSc are isoforms (different forms of the same protein).

Molecular models of the structure of: PrPC
Predominantly α-helix (3)

PrPSc β-sheets (40%), α-helix (30%)

Yeast prions
Prion-like proteins behaving in a similar way to PrP are found in some fungi. They have domains rich in asparagine and glutamine residues (important for the prion…...

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