Dopamine and Rotenone Modulate α-Synuclein Phase Separation and Liquid to Solid Transition.

Area of Science:

• Biophysics
• Neuroscience
• Molecular Biology

Background:

• Alpha-synuclein (α-Syn) liquid-liquid phase separation (LLPS) is critical in Parkinson's disease (PD) pathogenesis.
• Sporadic PD cases are linked to environmental factors like pesticides and metals, with dopamine and rotenone implicated in α-Syn pathology.

Purpose of the Study:

• To investigate how dopamine and rotenone influence α-Syn LLPS and aggregation.
• To elucidate the molecular mechanisms underlying α-Syn toxicity in PD.

Main Methods:

• In vitro studies of α-Syn LLPS kinetics and material properties.
• Cellular experiments exposing SH-SY5Y cells to dopamine and rotenone.
• Analysis of α-Syn oligomer and fibril formation and cytotoxicity.

Main Results:

• Both dopamine and rotenone promote α-Syn LLPS.
• Rotenone accelerates the liquid-to-solid transition, while dopamine delays solidification.
• Both toxicants increase cytotoxicity through distinct aggregation pathways, with rotenone promoting rapid fibrillation and dopamine causing delayed fibrillation.

Conclusions:

• Endogenous dopamine stress and environmental toxicants converge on α-Syn phase-separation dynamics.
• LLPS modulation by dopamine and rotenone represents a common pathway in PD pathogenesis.
• Understanding these mechanisms offers new insights into PD molecular processes.