# Modulation of α-Synuclein Oligomer and Aggregate Populations by pH and Metal Ions

## TL;DR

This study shows how pH and metal ions influence the formation of α-synuclein structures linked to diseases like Parkinson's.

## Contribution

The paper reveals how pH and metal ions dynamically modulate α-synuclein assembly states, offering new insights into disease mechanisms.

## Key findings

- α-synuclein forms different structures at acidic and neutral pH, with distinct assembly patterns.
- Metal ions like Fe3+, Cu2+, and Zn2+ strongly influence α-synuclein aggregation in a pH-dependent manner.
- Dynamic light scattering reveals pH-dependent redistribution of α-synuclein assembly mass.

## Abstract

α-Synuclein (α-syn) aggregation underlies synucleinopathies, yet the physicochemical determinants that govern which assembly states form under defined solution conditions remain incompletely resolved. Here, we examine how pH and metal ions reshape α-syn self-assembly. Across acidic and physiological pH conditions, α-syn populates monomeric, nanoscale oligomeric, and mesoscale aggregate states whose relative abundances evolve over time. Fluorescence microscopy reveals robust mesoscale assembly at pH 5, minimal aggregation at pH 7, and transient assemblies at pH 3, highlighting the limitations of imaging-based detection alone. Therefore, we use dynamic light scattering (DLS) to resolve oligomeric populations and quantify pH-dependent redistribution of assembly mass. Toxicity-mitigating modulators altered α-syn assembly in a strongly pH-dependent manner. Anle138b increased the abundance of oligomeric species at low pH, whereas EGCG produced divergent effects at pH 5 and pH 3. We further examined the effects of metal ions, finding that Fe3+ stabilized higher-order assemblies under acidic conditions, Cu2+ delayed assembly at pH 5 while enhancing aggregation at pH 3, and Zn2+ increased oligomerization primarily at low pH. Overall, these results demonstrate that α-syn assembly is highly sensitive to coupled effects of pH, metal chemistry, and time.