Quantifying Oligomer Populations in Real Time during Protein Aggregation Using Single-Molecule Mass Photometry

Area of Science:

• Biochemistry
• Neuroscience
• Biophysics

Background:

• Protein aggregation is central to neurodegenerative diseases.
• Early-stage oligomers are toxic but difficult to study due to transient states.

Purpose of the Study:

• To track populations of different oligomers during protein aggregation over time.
• To characterize previously inaccessible aggregation regimes and build quantitative models.

Main Methods:

• Utilized single-molecule mass photometry to measure individual oligomer masses in solution.
• Applied the technique to tau protein, relevant to Alzheimer's and frontotemporal dementia.

Main Results:

• Tau protein exists in equilibrium between monomers, dimers, and trimers before aggregation.
• Observed a drop in monomers, a rise in small oligomers, then incorporation into larger structures.
• Quantified microscopic rates and identified the most likely aggregation mechanism.

Conclusions:

• Single-molecule mass photometry offers a powerful method for studying protein aggregation dynamics.
• This approach enables the characterization of transient states and the development of mechanistic models for disease-related aggregation.