Plasminogen: A cellular protein cofactor for PrPSc propagation

Area of Science:

• Biochemistry
• Neuroscience
• Molecular Biology

Background:

• Prion diseases involve the misfolding and replication of prion protein (PrP) into the pathogenic PrPSc isoform.
• The mechanism of PrPSc propagation is not fully understood, with evidence suggesting a role for auxiliary factors.
• Plasminogen has been observed to interact with PrP, but its functional significance in PrPSc propagation was unknown.

Purpose of the Study:

• To investigate the role of plasminogen in the propagation of prion protein misfolded isoforms (PrPSc).
• To determine if plasminogen acts as a cellular auxiliary factor in PrPSc generation.

Main Methods:

• In vitro prion conversion assays were performed to measure PrPSc generation.
• Plasminogen concentration was varied, and its depletion or structural destabilization was tested.
• PrP-plasminogen interactions were manipulated.
• Cell culture models were used to confirm findings.

Main Results:

• Plasminogen substantially stimulated PrPSc propagation in a concentration-dependent manner.
• Accelerated PrPSc generation was observed in the presence of plasminogen.
• Depleting plasminogen, destabilizing its structure, or interfering with its interaction with PrP hindered PrPSc propagation.
• Increased PrPSc formation was confirmed in cell culture models.

Conclusions:

• Plasminogen is the first identified cellular protein auxiliary factor proven to stimulate PrPSc propagation.
• Plasminogen significantly accelerates the rate of PrPSc generation.
• Further research is needed to elucidate the molecular mechanisms underlying plasminogen's activity in prion propagation.