title: Downregulation of protein phosphatase 2A carboxyl methylation and methyltransferase may contribute to Alzheimer disease pathogenesis.
abstract: ABalphaC, a major protein phosphatase 2A (PP2A) heterotrimeric enzyme, binds to and regulates the microtubule cytoskeleton and tau. We have shown that ABalphaC protein expression levels are selectively reduced in Alzheimer disease (AD). Notably, the carboxyl methylation of PP2A catalytic subunit (PP2A(C)) is critically required for ABalphaC holoenzyme assembly, and catalyzed by a specific methyltransferase (PPMT). Here, we provide the first analysis of human PPMT and methylated PP2A(C) in brain regions from AD, non-AD demented, and aged control autopsy cases. Immunoblotting analyses revealed that PPMT protein expression and PP2A(C) 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.
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9073, USA. Estelle.Sontag@UTSouthwestern.edu
authors.forename: Estelle
authors.initials: E
authors.lastname: Sontag
authors.forename: Christa
authors.initials: C
authors.lastname: Hladik
authors.forename: Lisa
authors.initials: L
authors.lastname: Montgomery
authors.forename: Ampa
authors.initials: A
authors.lastname: Luangpirom
authors.forename: Ingrid
authors.initials: I
authors.lastname: Mudrak
authors.forename: Egon
authors.initials: E
authors.lastname: Ogris
authors.forename: Charles L
authors.initials: CL
authors.lastname: White
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology / Q000209:etiology*; D001921:Brain / Q000201:enzymology; D002102:Cadaver; D002245:Carbon Dioxide / Q000378:metabolism*; D016022:Case-Control Studies; D003704:Dementia / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation; D006801:Humans; D008745:Methylation; D008780:Methyltransferases / Q000378:metabolism*; D008875:Middle Aged; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D054648:Protein Phosphatase 2; D014018:Tissue Distribution; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016875:tau Proteins; D002245:Carbon Dioxide; C041069:carboxyl radical; D008780:Methyltransferases; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2