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.

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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 properties of the proteins) The mechanism of the propagation and aggregation of fungal prions have been studied revealing that, * * Prions are self-propagating amyloids leading to amyloidosis. Chaperones play a central role in the propagation of yeast prions; its role in the mammalian prion diseases is still unknown.

Prion aggregates (an electron microscope picture)

Ref: Google Images

Chaperones
HSP 104

Functions
Breaks protein aggregates

HSP 70-90 Complex

Suppression/Breaking of pathogenic aggregates

HSP 40

Protein unfolding activity, prevent formation of aggregates. Protect proteins from irreversible aggregation, prevent high temperature induced degradation, stabilization of target proteinchaperone interaction (cochaperonic activity)

HSP 26,31,41,42

How does a Prion Propogate?
• The generally accepted model for prion replication invokes the need for self-replicating particles that in some way seed the conversion of a prion protein to form its structurally distinct prion state. This is called as a Propagon.

• This is aided by an action of HSP104, HSP70.

Propogation is possible due to not being totally destroyed

Aggregates are completely destroyed hence no propogation

Can't propogate as it cannnot escape the cell confines

• While the above slide described how HSP104 gets used into propogating Prions, it is inside a single organism. • However there have been occurences,as to how the prions have been transmitted across different species. • For example,
– via blood transfusions (for Creutzfeldt-Jakob disease) – Consumption of infected tissues (cannibalism in New Guinea natives, eating of their relatives brain,Kuru) – Consumption of BSE-infected meat,leads to variant of CJD, affecting mid-adult population (normal affects the older ones,vCJD)

Diagnosis
1. Detection and Symptoms : The diseases are characterized by loss of motor control, dementia, paralysis, muscular atrophy and eventually death, typically following pneumonia. 2. Histopathology : Biopsy or Autopsy (confirmatory diagnosis): The typical neuropathology consists of a microscopic picture of spongiform changes, gliosis, and neuronal loss in the absence of inflammatory reaction. Amyloid plaques demonstrated in >>10% of patients.

3. PrPsc : The presence of PrPsc in biopsy or autopsy of brain samples can be demonstrated by immunodiagnostic tests, such as: a) immunohistochemical staining. b) Histoblot c) Western blot techniques d) Conformation-dependent immunoassay(CDI)

Summary
The prions are proteins that carry information for self-reproduction (contradict the central dogma of modern biology) The prions are expressed in cells of healthy humans and animals; their abnormal conformations (PrPSc) are insoluble, resistent to digestion and aggregate The PrPSc attacks the native prion PrPC, changes its conformation into an abnormal form and causes an exponential production of insoluble proteins; they aggregate and form the fibrillar structure Prion disease are rare fatal degenerative disorders; a portion of them can be transmitted; this mechanism is not clear (e.g. transmision of BSE to human)