Increased 14-3-3 phosphorylation observed in Parkinson's disease reduces neuroprotective potential of 14-3-3 proteins

NEUROBIOLOGY OF DISEASE

卷:79

Article

Slone, Sunny Rae¹  Lavalley, Nicholas¹  McFerrin, Michael¹  Wang, Bing¹  Yacoubian, Talene Alene¹ 

[1] Univ Alabama Birmingham, Dept Neurol, Ctr Neurodegenerat & Expt Therapeut, Birmingham, AL 35294 USA

关键词: 14-3-3 protein;    Parkinson disease;    Alpha-synuclein;    Rotenone;    Casein kinase;    MPP;    Neuroprotection;    Bax;    Cell death;    LRRK2;   

DOI  :  10.1016/j.nbd.2015.02.032

来源: Elsevier

【 摘 要 】

14-3-3 proteins are key regulators of cell survival. We have previously demonstrated that 14-3-3 levels are decreased in an alpha-synuclein (alpha syn) mouse model of Parkinson's disease (PD), and that overexpression of certain 14-3-3 isoforms is protective in several PD models. Here we examine whether changes in 14-3-3 phosphorylation may contribute to the neurodegenerative process in PD. We examine three key 14-3-3 phosphorylation sites that normally regulate 14-3-3 function, including serine 58 (S58), serine 184 (S184), and serine/threonine 232 (S/F232), in several models of PD and in human PD brain. We observed that an increase in S232 phosphorylation is observed in rotenone-treated neuroblastoma cells, in cells overexpressing asyn, and in human PD brains. Alterations in S58 phosphorylation were less consistent in these models, and we did not observe any phosphorylation changes at S184. Phosphorylation at S232 induced by rotenone is reduced by casein kinase inhibitors, and is not dependent on alpha syn. Mutation of the S232 site affected 14-3-3 theta's neuroprotective effects against rotenone and 1-methyl-4-phenylpyridinium (MPP+), with the S232D mutant lacking any protective effect compared to wildtype or S232A 14-3-3 theta. The S232D mutant partially reduced the ability of 14-3-3 theta to inhibit Bax activation in response to rotenone. Based on these findings, we propose that phosphorylation of 14-3-3s at serine 232 contributes to the neurodegenerative process in PD. (C) 2015 Elsevier Inc. All rights reserved.

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