@article{41c3d4e8d62046469f79e9d5e3a7e0e2,
title = "Synergistic neuroprotection by coffee components eicosanoyl-5-hydroxytryptamide and caffeine in models of Parkinson{\textquoteright}s disease and DLB",
abstract = " Hyperphosphorylated α-synuclein in Lewy bodies and Lewy neurites is a characteristic neuropathological feature of Parkinson{\textquoteright}s disease (PD) and Dementia with Lewy bodies (DLB). The catalytic subunit of the specific phosphatase, protein phosphatase 2A (PP2A) that dephosphorylates α-synuclein, is hypomethylated in these brains, thereby impeding the assembly of the active trimeric holoenzyme and reducing phosphatase activity. This phosphatase deficiency contributes to the accumulation of hyperphosphorylated α-synuclein, which tends to fibrillize more than unmodified α-synuclein. Eicosanoyl-5-hydroxytryptamide (EHT), a fatty acid derivative of serotonin found in coffee, inhibits the PP2A methylesterase so as to maintain PP2A in a highly active methylated state and mitigates the phenotype of α-synuclein transgenic (Syn Tg ) mice. Considering epidemiologic and experimental evidence suggesting protective effects of caffeine in PD, we sought, in the present study, to test whether there is synergy between EHT and caffeine in models of α-synucleinopathy. Coadmin-istration of these two compounds orally for 6 mo at doses that were individually ineffective in Syn Tg mice and in a striatal α-synuclein preformed fibril inoculation model resulted in reduced accumulation of phosphorylated α-synuclein, preserved neuronal integrity and function, diminished neuroinflammation, and improved behavioral performance. These indices were associated with increased levels of methylated PP2A in brain tissue. A similar profile of greater PP2A methylation and cytoprotection was found in SH-SY5Y cells cotreated with EHT and caffeine, but not with each compound alone. These findings suggest that these two components of coffee have synergistic effects in protecting the brain against α-synuclein−mediated toxicity through maintenance of PP2A in an active state. ",
keywords = "Dementia with Lewy bodies, Neuroprotection, Parkinson{\textquoteright}s disease, Phosphorylation, α-synuclein",
author = "Run Yan and Jie Zhang and Park, {Hye Jin} and Park, {Eun S.} and Stephanie Oh and Haiyan Zheng and Eunsung Junn and Michael Voronkov and Stock, {Jeffry B.} and Mouradian, {M. Maral}",
note = "Funding Information: ACKNOWLEDGMENTS. We thank Eliezer Masliah (then at the University of California, San Diego) for providing SynTg mice, and acknowledge technical assistance from Gina M. Moriarty in Jean Baum{\textquoteright}s laboratory (Rutgers University) with purifying recombinant mouse α-synuclein from plasmid pT7-7 originally obtained from Peter Lansbury. Technical assistance from Chelsea Bautista and Katherine Skibiel is also acknowledged. This study was supported by National Institutes of Health (NIH) Grant AT006868 (to M.M.M. and J.B.S.). Analyses conducted by the Rutgers Robert Wood Johnson Medical School Biological Mass Spectrometry Facility were supported by NIH Grant P30NS046593. E.J. is supported by NIH Grants NS070898 and NS095003 and the State of New Jersey. M.M.M. is the William Dow Lovett Professor of Neurology and is supported by the Michael J. Fox Foundation for Parkinson{\textquoteright}s Research, the American Parkinson Disease Association, the New Jersey Health Foundation/Nicholson Foundation, and NIH Grants NS073994, NS096032, and NS101134. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: We thank Eliezer Masliah (then at the University of California, San Diego) for providing SynTg mice, and acknowledge technical assistance from Gina M. Moriarty in Jean Baum{\textquoteright}s laboratory (Rutgers University) with purifying recombinant mouse α-synuclein from plasmid pT7-7 originally obtained from Peter Lansbury. Technical assistance from Chelsea Bautista and Katherine Skibiel is also acknowledged. This study was supported by National Institutes of Health (NIH) Grant AT006868 (to M.M.M. and J.B.S.). Analyses conducted by the Rutgers Robert Wood Johnson Medical School Biological Mass Spectrometry Facility were supported by NIH Grant P30NS046593. E.J. is supported by NIH Grants NS070898 and NS095003 and the State of New Jersey. M.M.M. is the William Dow Lovett Professor of Neurology and is supported by the Michael J. Fox Foundation for Parkinson{\textquoteright}s Research, the American Parkinson Disease Association, the New Jersey Health Foundation/Nicholson Foundation, and NIH Grants NS073994, NS096032, and NS101134. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2018 National Academy of Sciences. All Rights Reserved.",
year = "2018",
month = dec,
day = "18",
doi = "10.1073/pnas.1813365115",
language = "English (US)",
volume = "115",
pages = "E12053--E12062",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "51",
}