期刊
FRONTIERS IN CELLULAR NEUROSCIENCE
卷 7, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fncel.2013.00081
关键词
Parkinson'sdisease; alpha-synuclein; dopamine; autophagy; aggregation
资金
- National Institute of Health [P50-NS40256]
- Mayo Foundation
- Mangurian's Foundation
The formation of Lewy bodies containing alpha-synuclein (alpha-syn), prominent loss of dopaminergic neurons and dopamine (DA) deficiency in substantia nigra and striatum are histopathological and biochemical hallmarks of Parkinsons 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 alpha-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 alpha-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 alpha-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 alpha-syn and with or without exposure to LPO inducer-arachidonic acid (AA), plus 0500 mu M of DA were assessed for the levels of LPO, alpha-syn accumulation, cell viability, and autophagy. AA exposure elicited similar LPO levels in cells with and without alpha-syn overexpression, but significantly enhanced the accumulation of alpha-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 mu M) protected cells from AA cytotoxicity and alpha-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 mu M), 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 alpha-syn accumulation for statistical significance.
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