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 protein 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 eicosinoyl-5-hydroxytryptamide (EHT), 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, 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.

Dysregulation of protein phosphatase 2A in parkinson disease and dementia with lewy bodies

“…The ability of EHT, which prevents the demethylation of PP2A, in reducing α ‐synuclein phosphorylation and aggregation associated with improved neuropathological abnormalities and behavioral deficits in α ‐synuclein transgenic mice 13 supports this conclusion. Enhancing PP2A activity has also been shown to mitigate the pathology in an AD model as well: EHT treatment resulted in substantial amelioration of AD‐like pathologies such as tau hyperphosphorylation, elevated amyloid‐ β levels, and cognitive impairment in a rat model of AD generated by viral vector‐mediated expression of the PP2A endogenous inhibitor I2 PP2A , or SET protein, in the brain 19.…”

“…Considering the deleterious consequences of a dysfunctional PP2A, it is unlikely that the changes observed in these postmortem brain analyses represent a protective effect in surviving neurons. In relation to α ‐synucleinopathies in particular, PP2A catalyzes the dephosphorylation of phospho‐Ser 129 α ‐synuclein, and the methylation state of the PP2A C subunit regulates this activity 13. Accordingly, the finding of decreased PP2A methylation in this study provides a molecular mechanism for the reduced PP2A activity reported in α ‐synucleinopathies 16 and is likely a significant contributor to the hyperphosphorylation of aggregated α ‐synuclein in these disorders 10, 29…”

“…Since the main dephosphorylating enzyme of α ‐synuclein is the B55 α containing heterotrimeric isoform of PP2A,13 and methylation of the C subunit of PP2A enhances the incorporation of the regulatory B55 α subunit into the catalytically active holoenzyme,3, 4, 5 the markedly decreased expression of the methylating enzyme LCMT‐1 in these conditions, and increased expression of the demethylating enzyme PME‐1, lead to a striking decrease in the methylated form of PP2A. These dysregulatory changes are not only particularly prominent in the substantia nigra pars compacta but also present in the cortex.…”

“…We demonstrated previously in in vitro experiments and in cultured neuroblastoma cells that the main enzyme that dephosphorylates α ‐synuclein is the B55 α containing isoform of PP2A 13. We also identified a naturally occurring serotonin derivative in coffee, eicosanoyl‐5‐hydroxytryptamide (EHT), that inhibits PME‐1‐dependent PP2A demethylation, thereby stabilizing the PP2A heterotrimeric holoenzyme AB55 α C that dephosphorylates α ‐synuclein.…”

“…α ‐Synuclein is extensively phosphorylated at Ser 129 in PD and DLB brains 10, 11, 12. Additionally, hyperphosphorylated and misfolded α ‐synuclein accumulates in neurons of transgenic mice that express human α ‐synuclein,11, 13 and hyperphosphorylation exacerbates α ‐synuclein toxicity in Drosophila 14. In vitro, phosphorylation of α ‐synuclein at Ser 129 promotes its oligomerization and fibrillization 10…”