title: Alpha-Synuclein Fibrils Interact with Dopamine Reducing its Cytotoxicity on PC12 Cells.
abstract: 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.
authors.affiliation: Department of Industrial and Environmental Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran.
authors.forename: Masoome
authors.initials: M
authors.lastname: Khalife
authors.forename: Dina
authors.initials: D
authors.lastname: Morshedi
authors.forename: Farhang
authors.initials: F
authors.lastname: Aliakbari
authors.forename: Amir
authors.initials: A
authors.lastname: Tayaranian Marvian
authors.forename: Hossein
authors.initials: H
authors.lastname: Mohammad Beigi
authors.forename: Sadegh
authors.initials: S
authors.lastname: Azimzadeh Jamalkandi
authors.forename: Francisco
authors.initials: F
authors.lastname: Pan-Montojo
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects*; D004298:Dopamine / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D006801:Humans; D016716:PC12 Cells; D066329:Protein Aggregates; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*
chemical_list: D066329:Protein Aggregates; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D051844:alpha-Synuclein; D004298:Dopamine