{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T00:23:49Z","timestamp":1791073429700,"version":"4.1.0"},"reference-count":45,"publisher":"Society for Neuroscience","issue":"45","license":[{"start":{"date-parts":[[2009,5,5]],"date-time":"2009-05-05T00:00:00Z","timestamp":1241481600000},"content-version":"vor","delay-in-days":181,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2008,11,5]]},"abstract":"<jats:p>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\u03b1 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\u03b1, 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\u03b1 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\u03b1 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\u03b1-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\u03b1 could be beneficial for all tauopathies and folate-dependent disorders of the CNS.<\/jats:p>","DOI":"10.1523\/jneurosci.2816-08.2008","type":"journal-article","created":{"date-parts":[[2008,11,5]],"date-time":"2008-11-05T13:42:03Z","timestamp":1225892523000},"page":"11477-11487","source":"Crossref","is-referenced-by-count":66,"title":["Folate Deficiency Induces\n                    <i>In Vitro<\/i>\n                    and Mouse Brain Region-Specific Downregulation of Leucine Carboxyl Methyltransferase-1 and Protein Phosphatase 2A B\u03b1 Subunit Expression That Correlate with Enhanced Tau Phosphorylation"],"prefix":"10.1523","volume":"28","author":[{"given":"Jean-Marie","family":"Sontag","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viyada","family":"Nunbhakdi-Craig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Montgomery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erland","family":"Arning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teodoro","family":"Bottiglieri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estelle","family":"Sontag","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2008,11,5]]},"reference":[{"key":"2023041303345513000_28.45.11477.1","doi-asserted-by":"crossref","first-page":"219","DOI":"10.3233\/JAD-2007-11209","article-title":"Homocysteine 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