Aggregation of α-synuclein is kinetically controlled by intramolecular diffusion

Area of Science:

• Biochemistry
• Neuroscience
• Structural Biology

Background:

• Alpha-synuclein aggregation is implicated in Parkinson's disease pathogenesis.
• The initial steps of protein aggregation are not fully understood.
• Intrinsically disordered proteins like alpha-synuclein present unique challenges in studying aggregation.

Purpose of the Study:

• To investigate the role of backbone reconfiguration rate in the initial aggregation of alpha-synuclein.
• To determine how solvent conditions and mutations affect alpha-synuclein's intramolecular diffusion and aggregation propensity.

Main Methods:

• Utilized tryptophan-cysteine (Trp-Cys) quenching to measure intramolecular diffusion rates.
• Studied alpha-synuclein under varying temperatures, pH levels, and in the presence of the A30P mutation.
• Assessed aggregation rates under different solvent conditions.

Main Results:

• Intramolecular diffusion of alpha-synuclein is highly dependent on temperature and pH.
• Slower diffusion rates correlate with accelerated protein aggregation.
• The Parkinson's-associated A30P mutation slows down diffusion.
• Aggregation is faster at higher temperatures and lower pH, conditions that also slow diffusion.

Conclusions:

• The rate of backbone reconfiguration is a critical determinant of alpha-synuclein aggregation initiation.
• Modulating intramolecular diffusion could be a therapeutic strategy for Parkinson's disease.
• Understanding these early aggregation steps is key to developing preventative treatments.