Acute administration of L-DOPA induces changes in methylation metabolites, reduced protein phosphatase 2A methylation, and hyperphosphorylation of Tau protein in mouse brain.

Abstract

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.

• Authors: Teodoro Bottiglieri, Erland Arning, Brandi Wasek, Viyada Nunbhakdi-Craig, Jean-Marie Sontag, Estelle Sontag
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 32 Issue 27 Pg. 9173-81 (Jul 04 2012) ISSN: 1529-2401 [Electronic] United States
• PMID: 22764226 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antiparkinson Agents
• tau Proteins
• Levodopa
• Protein Phosphatase 2

Topics

• Animals
• Antiparkinson Agents (toxicity)
• Brain (drug effects, metabolism, pathology)
• Cell Line, Tumor
• Dopaminergic Neurons (drug effects, enzymology)
• Humans
• Levodopa (toxicity)
• Male
• Methylation (drug effects)
• Mice
• Mice, Inbred C57BL
• Nerve Degeneration (chemically induced, metabolism, physiopathology)
• Neuroblastoma
• Phosphorylation (drug effects, physiology)
• Primary Cell Culture
• Protein Phosphatase 2 (antagonists & inhibitors, metabolism)
• tau Proteins (agonists, biosynthesis, metabolism)