Journal article
Protein phosphatase 2A methyltransferase links homocysteine metabolism with tau and amyloid precursor protein regulation
The Journal of neuroscience, Vol.27(11), pp.2751-2759
03/14/2007
DOI: 10.1523/JNEUROSCI.3316-06.2007
PMCID: PMC6672573
PMID: 17360897
Abstract
Alzheimer's disease (AD) neuropathology is characterized by the accumulation of phosphorylated tau and amyloid-beta peptides derived from the amyloid precursor protein (APP). Elevated blood levels of homocysteine are a significant risk factor for many age-related diseases, including AD. Impaired homocysteine metabolism favors the formation of S-adenosylhomocysteine, leading to inhibition of methyltransferase-dependent reactions. Here, we show that incubation of neuroblastoma cells with S-adenosylhomocysteine results in reduced methylation of protein phosphatase 2A (PP2A), a major brain Ser/Thr phosphatase, most likely by inhibiting PP2A methyltransferase (PPMT). PP2A methylation levels are also decreased after ectopic expression of PP2A methylesterase in Neuro-2a (N2a) cells. Reduced PP2A methylation promotes the downregulation of B alpha-containing holoenzymes, thereby affecting PP2A substrate specificity. It is associated with the accumulation of both phosphorylated tau and APP isoforms and increased secretion of beta-secretase-cleaved APP fragments and amyloid-beta peptides. Conversely, incubation of N2a cells with S-adenosylmethionine and expression of PPMT enhance PP2A methylation. This leads to the accumulation of dephosphorylated tau and APP species and increased secretion of neuroprotective alpha-secretase-cleaved APP fragments. Remarkably, hyperhomocysteinemia induced in wild-type and cystathionine-beta-synthase +/- mice by feeding a high-methionine, low-folate diet is associated with increased brain S-adenosylhomocysteine levels, PPMT downregulation, reduced PP2A methylation levels, and tau and APP phosphorylation. We reported previously that downregulation of neuronal PPMT and PP2A methylation occur in affected brain regions from AD patients. The link between homocysteine, PPMT, PP2A methylation, and key CNS proteins involved in AD pathogenesis provides new mechanistic insights into this disorder.
Details
- Title: Subtitle
- Protein phosphatase 2A methyltransferase links homocysteine metabolism with tau and amyloid precursor protein regulation
- Creators
- Estelle Sontag - Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. estelle.sontag@utsouthwestern.eduViyada Nunbhakdi-CraigJean-Marie SontagRamon Diaz-ArrastiaEgon OgrisSanjana DayalSteven R LentzErland ArningTeodoro Bottiglieri
- Resource Type
- Journal article
- Publication Details
- The Journal of neuroscience, Vol.27(11), pp.2751-2759
- Publisher
- United States
- DOI
- 10.1523/JNEUROSCI.3316-06.2007
- PMID
- 17360897
- PMCID
- PMC6672573
- ISSN
- 0270-6474
- eISSN
- 1529-2401
- Grant note
- NS24621 / NINDS NIH HHS R01 HL063943 / NHLBI NIH HHS AT002311 / NCCIH NIH HHS AG12300 / NIA NIH HHS AG18883 / NIA NIH HHS AG17861 / NIA NIH HHS
- Language
- English
- Date published
- 03/14/2007
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984065487102771
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