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The Journal of Neuroscience, November 5, 2008, 28(45):11477-11487; doi:10.1523/JNEUROSCI.2816-08.2008

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Neurobiology of Disease
Folate Deficiency Induces In Vitro and Mouse Brain Region-Specific Downregulation of Leucine Carboxyl Methyltransferase-1 and Protein Phosphatase 2A B Subunit Expression That Correlate with Enhanced Tau Phosphorylation

Jean-Marie Sontag,¹ Viyada Nunbhakdi-Craig,¹ Lisa Montgomery,¹ Erland Arning,² Teodoro Bottiglieri,² and Estelle Sontag¹

¹Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, and ²Baylor University Medical Center, Institute of Metabolic Disease, Dallas, Texas 75226

Correspondence should be addressed to Dr. Estelle Sontag, Department of Pathology, University of Texas Southwestern, 5323 Harry Hines Boulevard, Dallas, TX 75390-9073. Email: estelle.sontag{at}utsouthwestern.edu

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 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, 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 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 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-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 could be beneficial for all tauopathies and folate-dependent disorders of the CNS.

Key words: folate; methylation; methylesterase; methyltransferase; PP2A; tau

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Received June 19, 2008; revised Sept. 4, 2008; accepted Sept. 23, 2008.

Correspondence should be addressed to Dr. Estelle Sontag, Department of Pathology, University of Texas Southwestern, 5323 Harry Hines Boulevard, Dallas, TX 75390-9073. Email: estelle.sontag{at}utsouthwestern.edu

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