title: 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: Institute of Metabolic Disease, Baylor Research Institute, Dallas, Texas 75226, USA. teodorob@baylorhealth.edu
authors: Teodoro
authors: T
authors: Bottiglieri
authors: Erland
authors: E
authors: Arning
authors: Brandi
authors: B
authors: Wasek
authors: Viyada
authors: V
authors: Nunbhakdi-Craig
authors: Jean-Marie
authors: JM
authors: Sontag
authors: Estelle
authors: E
authors: Sontag
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000633:toxicity; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007980:Levodopa / Q000633:toxicity*; D008297:Male; D008745:Methylation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D009447:Neuroblastoma; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D061251:Primary Cell Culture; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016875:tau Proteins / Q000819:agonists / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: D000978:Antiparkinson Agents; D016875:tau Proteins; D007980:Levodopa; D054648:Protein Phosphatase 2