- Title
- Acute administration of L-dopa induces changes in methylation metabolites, reduced protein phosphatase 2A methylation, and hyperphosphorylation of Tau protein in mouse brain
- Creator
- Bottiglieri, Teodoro; Arning, Erland; Wasek, Brandi; Nunbhakdi-Craig, Viyada; Sontag, Jean-Marie; Sontag, Estelle
- Relation
- Journal of Neuroscience Vol. 32, Issue 27, p. 9173-9181
- Publisher Link
- http://dx.doi.org/10.1523/jneurosci.0125-12.2012
- Publisher
- Society for Neuroscience
- Resource Type
- journal article
- Date
- 2012
- Description
- Folate deficiency and hypomethylation have been implicated in a number of age-related neurodegenerative disorders including dementia and Parkinson's disease (PD). Levodopa (l-dopa) therapy in PD patients has been shown to cause an increase in plasma total homocysteine as well as depleting cellular concentrations of the methyl donor, S-adenosylmethionine (SAM), and increasing the demethylated product S-adenosylhomocysteine (SAH). Modulation of the cellular SAM/SAH ratio can influence activity of methyltransferase enzymes, including leucine carboxyl methyltransferase that specifically methylates Ser/Thr protein phosphatase 2A (PP2A), a major Tau phosphatase. Here we show in human SH-SY5Y cells, in dopaminergic neurons, and in wild-type mice that l-dopa results in a reduced SAM/SAH ratio that is associated with hypomethylation of PP2A and increased phosphorylation of Tau (p-Tau) at the Alzheimer's disease-like PHF-1 phospho-epitope. The effect of l-dopa on PP2A and p-Tau was exacerbated in cells exposed to folate deficiency. In the folate-deficient mouse model, l-dopa resulted in a marked depletion of SAM and an increase in SAH in various brain regions with parallel downregulation of PP2A methylation and increased Tau phosphorylation. l-Dopa also enhanced demethylated PP2A amounts in the liver. These findings reveal a novel mechanism involving methylation-dependent pathways in l-dopa induces PP2A hypomethylation and increases Tau phosphorylation, which may be potentially detrimental to neuronal cells.
- Subject
- l-dopa; Parkinson’s disease; methylation metabolites
- Identifier
- http://hdl.handle.net/1959.13/1328755
- Identifier
- uon:25987
- Identifier
- ISSN:0270-6474
- Language
- eng
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