Prion protein conversion at two distinct cellular sites precedes fibrillisation

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Prion diseases are linked to the self-templating nature of prions, crucial for pathogenesis, infectivity, and transmissibility.
• Proteopathic seed propagation is recognized as a key pathogenic mechanism in many dementias, necessitating a deeper understanding of prion replication.

Purpose of the Study:

• To investigate the molecular mechanisms of prion replication.
• To differentiate the processes of de novo prion protein (PrP) conversion and fibril-like PrP aggregate formation.

Main Methods:

• Utilized highly discriminatory anti-PrP antibodies.
• Employed conversion-tolerant PrP chimera to study prion replication dynamics.

Main Results:

• De novo PrP conversion occurs rapidly (minutes) at two subcellular locations.
• Fibril-like PrP aggregates form slowly (hours) exclusively at the plasma membrane.
• Distinct PrP pools at perinuclear sites and the plasma membrane exhibit differential N-terminal processing, aggregation, and fibril formation.

Conclusions:

• De novo PrP conversion and fibril formation are mechanistically and kinetically distinct processes.
• Abnormal PrP pools are linked via exocytic transport, involving synaptic and large-dense core vesicles.
• Understanding these distinct pathways is vital for delineating common and specific disease mechanisms in prion disorders and related dementias.