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.