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 autophagic-lysosomal 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.
Highlights
Parkinson’s disease (PD) is characterized by accumulation of neuronal inclusions containing α-synuclein (α-syn), degeneration of dopaminergic neurons and deficiency of dopamine (DA) in substantia nigra and striatum (Dauer and Przedborski, 2003)
Multiple lines of evidence have indicated that enhanced production of reactive oxygen species (ROS) is a critical pathogenic factor causing PD and that ROS can be generated via autoxidation of DA (Jenner, 1991; Fahn and Cohen, 1992; Lotharius and Brundin, 2002; Tieu et al, 2003)
It is worth noting that very low expression of DA transporter (DAT) in mock transfectant can be detected by western blotting but not immunocytochemistry might be due to the difference of sensitivity between them
Summary
Parkinson’s disease (PD) is characterized by accumulation of neuronal inclusions containing α-synuclein (α-syn), degeneration of dopaminergic neurons and deficiency of dopamine (DA) in substantia nigra and striatum (Dauer and Przedborski, 2003). Besides α-syn accumulation, AA exposure resulted in increase of caspase 3 activation (Figures 3A,D) and decrease of the viability of Tet-Off-induced cells (Figure 3E) in a time-dependent manner.
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