Dopamine prevents lipid peroxidation-induced accumulation of toxic α-synuclein oligomers by preserving autophagy-lysosomal function

Peizhou Jiang, Ming Gan, Shu Hui C. Yen

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

The formation of Lewy bodies containing α-synuclein (α-syn), prominent loss of dopaminergic neurons and dopamine (DA) deficiency in substantia nigra and striatum are histopathological and biochemical hallmarks of Parkinson's disease (PD). Multiple lines of evidence have indicated that a critical pathogenic factor causing PD is enhanced production of reactive oxygen species (ROS), which reacts readily with polyunsaturated fatty acids to cause lipid peroxidation (LPO). LPO products have been shown to facilitate assembly of toxic α-syn oligomers in in vitro studies. Since DA is prone to autoxidation and cause ROS, it has been suggested that interactions among DA, LPO, and α-syn play an important role in neuronal loss in PD. However, the exact mechanism(s) remains unclear. We addressed this issue using a neuronal cell model which inducibly expresses human wild-type α-syn by the tetracycline off (Tet-Off) mechanism and stably expresses high levels of DA transporter. Under retinoic acid elicited neuronal differentiation, cells with or without overexpressing α-syn and with or without exposure to LPO inducer-arachidonic acid (AA), plus 0-500 μM of DA were assessed for the levels of LPO, α-syn accumulation, cell viability, and autophagy. AA exposure elicited similar LPO levels in cells with and without α-syn overexpression, but significantly enhanced the accumulation of α-syn oligomers and monomers only in cultures with Tet-Off induction and decreased cell survival in a LPO-dependent manner. Surprisingly, DA at low concentrations (<50 μM) protected cells from AA cytotoxicity and α-syn accumulation. Such effects were attributed to the ability of DA to preserve autophagiclysosomal function compromised by the AA exposure. At high concentrations (>100 μM), DA exposure enhanced the toxic effects of AA. To our knowledge, this is the first report showing biphasic effects of DA on neuronal survival and α-syn accumulation.

Original languageEnglish (US)
JournalFrontiers in Cellular Neuroscience
Issue numberMAY
DOIs
StatePublished - 2013

Keywords

  • Aggregation
  • Autophagy
  • Dopamine
  • Parkinson's disease
  • α-synuclein

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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