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.