Enhanced phosphatase activity attenuates α-synucleinopathy in a mouse model

Kang Woo Lee, Walter Chen, Eunsung Junn, Joo Young Im, Hilary Grosso, Patricia K. Sonsalla, Xuyan Feng, Neelanjana Ray, Jose R. Fernandez, Yang Chao, Eliezer Masliah, Michael Voronkov, Steven P. Braithwaite, Jeffry B. Stock, M. Maral Mouradian

Research output: Contribution to journalArticlepeer-review

148 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)6963-6971
Number of pages9
JournalJournal of Neuroscience
Issue number19
StatePublished - May 11 2011

All Science Journal Classification (ASJC) codes

  • General Neuroscience


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