Alpha-Synuclein Fibrils Interact with Dopamine Reducing its Cytotoxicity on PC12 Cells
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Aggregated alpha-synuclein (α-SYN) is the major component of Lewy bodies and Lewy neurites, two of the pathological hallmarks of Parkinson’s disease (PD). Aggregation of α-SYN leads to toxic species involved in the degeneration of dopaminergic neurons in the midbrain. Different studies suggest a strong association between the presence of dopamine (DA) and the cell specific degeneration caused by α-SYN aggregates in PD. Despite extensive studies on the effect of DA on α-SYN fibrillation, it remains unclear how the simultaneous presence of DA and α-SYN influences the degeneration of dopaminergic neurons. In this study we show that separate treatments with specific doses of DA or early stage α-SYN aggregates (ESAA) are both cytotoxic to PC12 cells. Surprisingly, simultaneous treatment of cells with DA and ESAA significantly decreased this toxicity. This cytotoxicity was further reduced by the presence of heavier particles of α-SYN aggregates with more fibrillogenic characteristics. Spectrometric analysis revealed that α-SYN fibrils interact with DA even after the sample was dialyzed for 48 h, suggesting a strong interaction. Interestingly, digestion of unprotected N- and C-α-SYN-fibril terminals by proteinase K did not affect this interaction. Our results suggest that fibrillar forms of α-SYN with localized expanded active surfaces may interact with DA and moderate its cytotoxicity. Thus, highlighting the importance of fibrillar proteins in developing clinical approaches for amyloid diseases.
Keywordsα-Synuclein Dopamine Fibrillation Fluorescent labeled α-synuclein, Neurodegeneration Parkinson’s disease Reactive oxygen species (ROS)
Atomic Force Microscopy
Early Stages α-SYN Aggregates
Fourier Transform infrared
3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide
Reactive Oxygen Species
Substantia Nigra pars compacta
This work was supported by the National Institute of Genetic Engineering and Biotechnology.
Compliance with Ethical Standards
Conflict of interest
The authors declare no potential conflict of interest.
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