Downregulation of Protein Phosphatase 2A Carboxyl Methylation and Methyltransferase May Contribute to Alzheimer Disease Pathogenesis

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...

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Bibliographic Details
Published in:Journal of neuropathology and experimental neurology 2004-10, Vol.63 (10), p.1080-1091
Main Authors: SONTAG, ESTELLE, HLADIK, CHRISTA, MONTGOMERY, LISA, LUANGPIROM, AMPA, MUDRAK, INGRID, OGRIS, EGON, WHITE, CHARLES L
Format: Article
Language:English
Subjects:
Aged
Aged, 80 and over
Alzheimer Disease - enzymology
Alzheimer Disease - etiology
Biological and medical sciences
Brain - enzymology
Cadaver
Carbon Dioxide - metabolism
Case-Control Studies
Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
Dementia - enzymology
Dementia - metabolism
Dementia - pathology
Disorders of higher nervous function. Focal brain diseases. Central vestibular syndrome and deafness. Brain stem syndromes
Down-Regulation
Humans
Medical sciences
Methylation
Methyltransferases - metabolism
Middle Aged
Nervous system (semeiology, syndromes)
Neurology
Phosphoprotein Phosphatases - metabolism
Phosphorylation
Protein Phosphatase 2
tau Proteins - metabolism
Tissue Distribution
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Summary: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.
ISSN:0022-3069
1554-6578
DOI:10.1093/jnen/63.10.1080