RT Journal Article SR Electronic T1 Enhanced Phosphatase Activity Attenuates α-Synucleinopathy in a Mouse Model JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 6963 OP 6971 DO 10.1523/JNEUROSCI.6513-10.2011 VO 31 IS 19 A1 Lee, Kang-Woo A1 Chen, Walter A1 Junn, Eunsung A1 Im, Joo-Young A1 Grosso, Hilary A1 Sonsalla, Patricia K. A1 Feng, Xuyan A1 Ray, Neelanjana A1 Fernandez, Jose R. A1 Chao, Yang A1 Masliah, Eliezer A1 Voronkov, Michael A1 Braithwaite, Steven P. A1 Stock, Jeffry B. A1 Mouradian, M. Maral YR 2011 UL http://www.jneurosci.org/content/31/19/6963.abstract AB 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.