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

Riya Bera1, Shouvik Manna1, Ranjit Shaw1

  • 1Department of Biosciences and Bioengineering, IIT Bombay, Mumbai, India.

Small (Weinheim an Der Bergstrasse, Germany)
|March 12, 2026
PubMed
Summary
This summary is machine-generated.

Parkinson's disease (PD) involves alpha-synuclein (α-Syn) aggregation. This study shows dopamine and rotenone promote α-Syn liquid-liquid phase separation (LLPS), a key step in PD pathology, leading to increased cytotoxicity.

Keywords:
Parkinson's diseasealpha‐Synucleindopaminephase separationrotenone

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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.