title: Folate deficiency induces in vitro and mouse brain region-specific downregulation of leucine carboxyl methyltransferase-1 and protein phosphatase 2A B(alpha) subunit expression that correlate with enhanced tau phosphorylation.
abstract: Altered folate homeostasis is associated with many clinical and pathological manifestations in the CNS. Notably, folate-mediated one-carbon metabolism is essential for methyltransferase-dependent cellular methylation reactions. Biogenesis of protein phosphatase 2A (PP2A) holoenzyme containing the regulatory B(alpha) subunit, a major brain tau phosphatase, is controlled by methylation. Here, we show that folate deprivation in neuroblastoma cells induces downregulation of PP2A leucine carboxyl methyltransferase-1 (LCMT-1) expression, resulting in progressive accumulation of newly synthesized demethylated PP2A pools, concomitant loss of B(alpha), and ultimately cell death. These effects are further accentuated by overexpression of PP2A methylesterase (PME-1) but cannot be rescued by PME-1 knockdown. Overexpression of either LCMT-1 or B(alpha) is sufficient to protect cells against the accumulation of demethylated PP2A, increased tau phosphorylation, and cell death induced by folate starvation. Conversely, knockdown of either protein accelerates folate deficiency-evoked cell toxicity. Significantly, mice maintained for 2 months on low-folate or folate-deficient diets have brain-region-specific alterations in metabolites of the methylation pathway. Those are associated with downregulation of LCMT-1, methylated PP2A, and B(alpha) expression and enhanced tau phosphorylation in susceptible brain regions. Our studies provide novel mechanistic insights into the regulation of PP2A methylation and tau. They establish LCMT-1- and B(alpha)-containing PP2A holoenzymes as key mediators of the role of folate in the brain. Our results suggest that counteracting the neuronal loss of LCMT-1 and B(alpha) could be beneficial for all tauopathies and folate-dependent disorders of the CNS.
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9073, USA. estelle.sontag@utsouthwestern.edu
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Sontag
authors.forename: Viyada
authors.initials: V
authors.lastname: Nunbhakdi-Craig
authors.forename: Lisa
authors.initials: L
authors.lastname: Montgomery
authors.forename: Erland
authors.initials: E
authors.lastname: Arning
authors.forename: Teodoro
authors.initials: T
authors.lastname: Bottiglieri
authors.forename: Estelle
authors.initials: E
authors.lastname: Sontag
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002265:Carboxylic Ester Hydrolases / Q000502:physiology; D016923:Cell Death / Q000502:physiology; D002461:Cell Line, Transformed; D015536:Down-Regulation / Q000502:physiology*; D005494:Folic Acid Deficiency / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011497:Protein O-Methyltransferase / Q000378:metabolism*; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016875:tau Proteins; D012694:Serine; D011497:Protein O-Methyltransferase; D002265:Carboxylic Ester Hydrolases; C119357:protein phosphatase methylesterase-1; C117094:Ppp2r3a protein, mouse; D054648:Protein Phosphatase 2