Language

English

Publication Date

2-20-2026

Journal

Biomolecules

DOI

10.3390/biom16020326

PMID

41750396

PMCID

PMC12938058

PubMedCentral® Posted Date

2-20-2026

PubMedCentral® Full Text Version

Post-print

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.

Keywords

alpha-Synuclein, Hydrogen-Ion Concentration, Protein Aggregates, Humans, Metals, Protein Multimerization, Zinc, Ions, α-synuclein, synucleinopathies, protein aggregation, protein self-assembly, pH, metal ions, neurodegeneration

Published Open-Access

yes

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