Downregulation of protein phosphatase 2A carboxyl methylation and methyltransferase may contribute to Alzheimer disease pathogenesis

Estelle Sontag, Christa Hladik, Lisa Montgomery, Ampa Luangpirom, Ingrid Mudrak, Egon Ogris, Charles L. White

Research output: Contribution to journalArticle

136 Citations (Scopus)

Abstract

ABαC, a major protein phosphatase 2A (PP2A) heterotrimeric enzyme, binds to and regulates the microtubule cytoskeleton and tau. We have shown that ABαC protein expression levels are selectively reduced in Alzheimer disease (AD). Notably, the carboxyl methylation of PP2A catalytic subunit (PP2AC) is critically required for ABαC holoenzyme assembly, and catalyzed by a specific methyltransferase (PPMT). Here, we provide the first analysis of human PPMT and methylated PP2AC in brain regions from AD, non-AD demented, and aged control autopsy cases. Immunoblotting analyses revealed that PPMT protein expression and PP2AC methylation levels were quantitatively decreased in AD-affected brain regions. Immunohistochemical studies showed that PPMT was abundant in neurons throughout the cortex in normal control and non-AD demented cases. However, in AD, there was a regional loss of PPMT immunoreactivity that closely paralleled the severity of tau pathology, but not amyloid plaque burden. We propose that the deregulation of PPMT and PP2A methylation/demethylation cycles contributes to AD pathogenesis, by inducing changes in PP2A heteromultimeric composition and substrate specificity. In turn, PP2A dysfunction compromises the mechanisms that control tau, neuronal plasticity, and survival.

Original languageEnglish (US)
Pages (from-to)1080-1091
Number of pages12
JournalJournal of Neuropathology and Experimental Neurology
Volume63
Issue number10
StatePublished - Oct 2004

Fingerprint

Protein Phosphatase 2
Methyltransferases
Methylation
Alzheimer Disease
Down-Regulation
Catalytic Domain
Holoenzymes
Neuronal Plasticity
Amyloid Plaques
Brain
Substrate Specificity
Cytoskeleton
Immunoblotting
Microtubules
Autopsy
Proteins
Pathology
Neurons
Survival
Enzymes

Keywords

  • Alzheimer disease
  • Amyloid
  • Brain
  • Methylation
  • Methyltransferase
  • PP2A
  • Tau

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neuroscience(all)

Cite this

Downregulation of protein phosphatase 2A carboxyl methylation and methyltransferase may contribute to Alzheimer disease pathogenesis. / Sontag, Estelle; Hladik, Christa; Montgomery, Lisa; Luangpirom, Ampa; Mudrak, Ingrid; Ogris, Egon; White, Charles L.

In: Journal of Neuropathology and Experimental Neurology, Vol. 63, No. 10, 10.2004, p. 1080-1091.

Research output: Contribution to journalArticle

Sontag, Estelle ; Hladik, Christa ; Montgomery, Lisa ; Luangpirom, Ampa ; Mudrak, Ingrid ; Ogris, Egon ; White, Charles L. / Downregulation of protein phosphatase 2A carboxyl methylation and methyltransferase may contribute to Alzheimer disease pathogenesis. In: Journal of Neuropathology and Experimental Neurology. 2004 ; Vol. 63, No. 10. pp. 1080-1091.
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