PT - JOURNAL ARTICLE AU - Lee, Kang-Woo AU - Chen, Walter AU - Junn, Eunsung AU - Im, Joo-Young AU - Grosso, Hilary AU - Sonsalla, Patricia K. AU - Feng, Xuyan AU - Ray, Neelanjana AU - Fernandez, Jose R. AU - Chao, Yang AU - Masliah, Eliezer AU - Voronkov, Michael AU - Braithwaite, Steven P. AU - Stock, Jeffry B. AU - Mouradian, M. Maral TI - Enhanced Phosphatase Activity Attenuates α-Synucleinopathy in a Mouse Model AID - 10.1523/JNEUROSCI.6513-10.2011 DP - 2011 May 11 TA - The Journal of Neuroscience PG - 6963--6971 VI - 31 IP - 19 4099 - http://www.jneurosci.org/content/31/19/6963.short 4100 - http://www.jneurosci.org/content/31/19/6963.full SO - J. Neurosci.2011 May 11; 31 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.