Calcium promotes α-synuclein liquid-liquid phase separation to accelerate amyloid aggregation

Area of Science:

• Neuroscience
• Biochemistry
• Protein aggregation

Background:

• Alpha-synuclein (α-Syn) aggregation in Lewy bodies is central to Parkinson's disease (PD).
• Calcium dysregulation is a known risk factor for PD, and Ca²⁺ is known to interact with α-Syn.
• The precise mechanism by which Ca²⁺ influences α-Syn aggregation remains elusive.

Purpose of the Study:

• To elucidate the role of Ca²⁺ in modulating α-Syn aggregation.
• To investigate the impact of Ca²⁺ on α-Syn phase separation and subsequent amyloid formation.
• To explore the interaction between Ca²⁺-bound α-Syn droplets and lipid membranes.

Main Methods:

• Observation of Ca²⁺ effects on α-Syn liquid droplet formation and fusion.
• Utilizing metal chelators to assess the reversibility of Ca²⁺-induced changes.
• Investigating Ca²⁺-induced α-Syn phase separation in the presence of lipid membranes.
• Assessing the recruitment of lipid vesicles by Ca²⁺/α-Syn droplets.

Main Results:

• Ca²⁺ significantly accelerates α-Syn amyloid aggregation by promoting protein phase separation.
• Ca²⁺ enhances the formation of α-Syn liquid droplets, which retain fluidity and fusion capabilities.
• The Ca²⁺-induced effects on droplet size were reversible with a metal chelator, indicating LLPS modulation.
• Ca²⁺ promoted α-Syn phase separation even with lipid membranes present, and Ca²⁺/α-Syn droplets recruited lipid vesicles.

Conclusions:

• Ca²⁺ facilitates α-Syn phase separation, thereby accelerating amyloid aggregation.
• This mechanism provides a potential link between calcium dysregulation and α-Syn accumulation in Parkinson's disease.
• Understanding Ca²⁺'s role in α-Syn LLPS offers new therapeutic targets for PD.