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Linking alpha-synuclein phosphorylation to reactive oxygen species formation and mitochondrial dysfunction in SH-SY5Y cells

Lookup NU author(s): Professor Tiago Outeiro

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Abstract

Alpha-synuclein (α-syn) is a soluble protein highly enriched in presynaptic terminals of neurons. Accumulation of α-syn as intracellular filamentous aggregates is a pathological feature of sporadic and familial forms of Parkinson's disease (PD). Changes in α-syn post-translational modifications, as well as mitochondrial dysfunction and oxidative stress constitute key pathogenic events of this disorder. Here we assessed the correlation between α-syn phosphorylation at serine 129 (Ser129), the formation of reactive oxygen species (ROS) and mitochondrial dysfunction in SH-SY5Y cells expressing A53T mutant or wild-type (WT) α-syn, exposed to ferrous iron (FeSO4) and rotenone (complex I inhibitor). Under basal conditions, prolonged expression of A53T mutant α-syn altered mitochondria morphology, increased superoxide formation and phosphorylation at Ser129, which was linked to decreased activity of protein phosphatase 2A (PP2A). Exposure to FeSO4 or rotenone enhanced intracellular ROS levels, including superoxide anions, in both types of cells, along with α-syn Ser129 phosphorylation and mitochondrial depolarization. Most of these changes were largely evident in A53T mutant α-syn expressing cells. Overall, the data suggest that stimuli that promote ROS formation and mitochondrial alterations highly correlate with mutant α-syn phosphorylation at Ser129, which may precede cell degeneration in PD. © 2014 Elsevier Inc.


Publication metadata

Author(s): Perfeito R, Lazaro DF, Outeiro TF, Rego AC

Publication type: Article

Publication status: Published

Journal: Molecular and Cellular Neuroscience

Year: 2014

Volume: 62

Pages: 51-59

Print publication date: 01/09/2014

Online publication date: 07/08/2014

Acceptance date: 06/08/2014

ISSN (print): 1044-7431

ISSN (electronic): 1095-9327

Publisher: Academic Press Inc.

URL: https://doi.org/10.1016/j.mcn.2014.08.002

DOI: 10.1016/j.mcn.2014.08.002

PubMed id: 25109238


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