α-Synuclein Aggregation in Saccharomyces Cerevisiae: An Experimental Analysis of Comorbidity in PD and Synucleinopathies

Overview

α-synuclein aggregation is a hallmark of Parkinsonian disorders, where the normally flexible protein misfolds into β-sheet–rich fibrils that disrupt cells. Despite its importance, the specific mechanisms by which stressors influence α-synuclein aggregation at both chemical and cellular levels remain unclear. In this study, I used a Saccharomyces cerevisiae system expressing α-synuclein to explore how oxidative stress (hydrogen peroxide), metabolic stress (high glucose levels), and thermal stress (higher temperatures) change aggregation behavior, protein modifications, and cellular toxicity. When hydrogen peroxide was added, it generated reactive oxygen species through reactions like Fenton chemistry (H₂O₂ + Fe²⁺ → Fe³⁺ + OH⁻ + • OH), oxidizing methionine (Met → MetO), crosslinking tyrosines (Tyr–Tyr), and adding nitration marks (Tyr → 3-nitrotyrosine). These chemical alterations induced α-synuclein to adopt misfolded, oligomeric conformations, challenging yeast cells with redox imbalance (2 GSH + H₂O₂ → GSSG + 2 H₂O) and proteotoxic stress. Elevated glucose levels initiated glycation (lysine + glucose → Schiff base → Amadori product → AGEs), thereby stabilizing aggregation-prone intermediates, while yeast metabolism generated reactive byproducts like methylglyoxal, compromising protein degradation. Increased temperature accelerated molecular motion and hydrophobic interactions, diminishing the energy barrier for fibril formation (α-synucleinₙ + α-synuclein → α-synucleinₙ₊₁). Across all conditions, α-synuclein aggregated through hydrogen bonding, π–π stacking, and hydrophobic collapse, forming fibrils and inclusions. Oxidative stress caused rapid, highly toxic aggregates, metabolic stress produced persistent chemically modified aggregates, and heat accelerated aggregation. These results highlight the impact of specific chemical and environmental pressures on α-synuclein behavior and cellular health, providing deeper insights into the mechanisms underlying Parkinsonian disorders.

Competition history

• CSEF 2026 Biochemistry/ Molecular Biology (Senior Division) · Entry S-04-02

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