title: Enhanced phosphatase activity attenuates α-synucleinopathy in a mouse model.
abstract: α-Synuclein (α-Syn) is a key protein that accumulates as hyperphosphorylated aggregates in pathologic hallmark features of Parkinson's disease (PD) and other neurodegenerative disorders. Phosphorylation of this protein at serine 129 is believed to promote its aggregation and neurotoxicity, suggesting that this post-translational modification could be a therapeutic target. Here, we demonstrate that phosphoprotein phosphatase 2A (PP2A) dephosphorylates α-Syn at serine 129 and that this activity is greatly enhanced by carboxyl methylation of the catalytic C subunit of PP2A. α-Syn-transgenic mice raised on a diet supplemented with eicosanoyl-5-hydroxytryptamide, an agent that enhances PP2A methylation, dramatically reduced both α-Syn phosphorylation at Serine 129 and α-Syn aggregation in the brain. These biochemical changes were associated with enhanced neuronal activity, increased dendritic arborizations, and reduced astroglial and microglial activation, as well as improved motor performance. These findings support the notion that serine 129 phosphorylation of α-Syn is of pathogenetic significance and that promoting PP2A activity is a viable disease-modifying therapeutic strategy for α-synucleinopathies such as PD.
authors.affiliation: Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.
authors.forename: Kang-Woo
authors.initials: KW
authors.lastname: Lee
authors.forename: Walter
authors.initials: W
authors.lastname: Chen
authors.forename: Eunsung
authors.initials: E
authors.lastname: Junn
authors.forename: Joo-Young
authors.initials: JY
authors.lastname: Im
authors.forename: Hilary
authors.initials: H
authors.lastname: Grosso
authors.forename: Patricia K
authors.initials: PK
authors.lastname: Sonsalla
authors.forename: Xuyan
authors.initials: X
authors.lastname: Feng
authors.forename: Neelanjana
authors.initials: N
authors.lastname: Ray
authors.forename: Jose R
authors.initials: JR
authors.lastname: Fernandez
authors.forename: Yang
authors.initials: Y
authors.lastname: Chao
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Michael
authors.initials: M
authors.lastname: Voronkov
authors.forename: Steven P
authors.initials: SP
authors.lastname: Braithwaite
authors.forename: Jeffry B
authors.initials: JB
authors.lastname: Stock
authors.forename: M Maral
authors.initials: MM
authors.lastname: Mouradian
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002478:Cells, Cultured; D003712:Dendrites / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D008745:Methylation; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D012701:Serotonin / Q000031:analogs & derivatives* / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein; C000602511:eicosanoyl-5-hydroxytryptamide; D012701:Serotonin; D010749:Phosphoprotein Phosphatases