Early stage prion assembly involves two subpopulations with different quaternary structures and a secondary...

Area of Science:

• Biochemistry
• Neuroscience
• Molecular Biology

Background:

• Neurodegenerative diseases like Alzheimer's and Parkinson's involve misfolded proteins forming distinct assemblies or strains.
• The emergence and coevolution of these structurally distinct protein assemblies remain mechanistically unclear.
• Intrastrain structural heterogeneity within these protein assemblies is increasingly acknowledged.

Purpose of the Study:

• To elucidate the mechanistic processes underlying the structural diversification of protein assemblies in prion diseases.
• To understand how different protein strains emerge and coevolve during early prion replication.
• To investigate the role of protein structure in prion adaptation and toxicity.

Main Methods:

• Investigated early prion replication dynamics.
• Analyzed the formation of structurally distinct protein assemblies.
• Examined the role of the prion protein in templating pathways.

Main Results:

• Early prion replication generates two distinct subsets of protein assemblies via two sequential formation processes.
• The first process involves quaternary structural convergence, reducing polydispersity to form small oligomers.
• The second process utilizes a secondary autocatalytic templating pathway, dependent on the prion protein, to enlarge these oligomers.

Conclusions:

• A two-step mechanism explains the generation of structurally diverse prion assemblies.
• This pathway provides novel mechanistic insights into prion structural diversification.
• Understanding these processes is crucial for comprehending prion adaptation and neurotoxicity.