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

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

doi:10.1093/jnen/63.10.1080

Cited by 182 publications

(153 citation statements)

References 46 publications

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“…Elevated plasma levels of homocysteine are a risk factor for AD, and brain S-adenosylmethionine levels are severely reduced in AD. Consistent with this observation, LCMT1 downregulation associated with reduced PR55/Ba expression has been observed in AD brains and shown to contribute to Tau hyperphosphorylation and neurodegeneration [61]. Similarly, in mice, hyperhomocysteinemia-induced increased levels of brain S-adenosylhomocysteine is associated with reduced PP2A methylation [62].…”

Section: Reviewsupporting

confidence: 59%

PP2A holoenzyme assembly: in cauda venenum (the sting is in the tail)

Janssens

Longin

Goris

2008

Trends in Biochemical Sciences

366

424

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Section: Reviewsupporting

confidence: 59%

PP2A holoenzyme assembly: in cauda venenum (the sting is in the tail)

Janssens

Longin

Goris

2008

Trends in Biochemical Sciences

366

424

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“…8 and 9). Impaired methyl-donor metabolism is a risk factor for AD (10, 11), and PP2A dysregulation caused by impaired methylation is thought to be one of the molecular mechanisms contributing to this increased risk (12)(13)(14). Methylation promotes the formation of PP2A holoenzymes that contain Bα regulatory subunits (7,13,(15)(16)(17)(18)(19), and these forms of PP2A exhibit the greatest tau phosphatase activity (6, 7).…”

mentioning

confidence: 99%

PP2A methylation controls sensitivity and resistance to β-amyloid–induced cognitive and electrophysiological impairments

Nicholls

Sontag

Zhang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Elevated levels of the β-amyloid peptide (Aβ) are thought to contribute to cognitive and behavioral impairments observed in Alzheimer's disease (AD). Protein phosphatase 2A (PP2A) participates in multiple molecular pathways implicated in AD, and its expression and activity are reduced in postmortem brains of AD patients. PP2A is regulated by protein methylation, and impaired PP2A methylation is thought to contribute to increased AD risk in hyperhomocysteinemic individuals. To examine further the link between PP2A and AD, we generated transgenic mice that overexpress the PP2A methylesterase, protein phosphatase methylesterase-1 (PME-1), or the PP2A methyltransferase, leucine carboxyl methyltransferase-1 (LCMT-1), and examined the sensitivity of these animals to behavioral and electrophysiological impairments caused by exogenous Aβ exposure. We found that PME-1 overexpression enhanced these impairments, whereas LCMT-1 overexpression protected against Aβ-induced impairments. Neither transgene affected Aβ production or the electrophysiological response to low concentrations of Aβ, suggesting that these manipulations selectively affect the pathological response to elevated Aβ levels. Together these data identify a molecular mechanism linking PP2A to the development of AD-related cognitive impairments that might be therapeutically exploited to target selectively the pathological effects caused by elevated Aβ levels in AD patients.M ultiple observations suggest a role for the serine/threonine protein phosphatase 2A (PP2A) in the molecular pathways that underlie Alzheimer's disease (AD). Analyses conducted on postmortem AD brains have found reduced PP2A expression and activity, and studies conducted in animal models have found that inhibiting PP2A produces AD-like tau pathology and cognitive impairment (1-3). One of the ways in which PP2A may affect AD is through its role as the principal tau phosphatase (4-7). PP2A also interacts with a number of kinases implicated in AD including glycogen synthase kinase 3β (GSK3β), cyclindependent kinase 5 (CDK5), and ERK and JNK as well as amyloid precursor protein and the NMDA and metabotropic glutamate receptors (reviewed in ref.2).PP2A is a heterotrimeric protein composed of a catalytic, scaffolding, and regulatory subunit. Each subunit is encoded by multiple genes and splice isoforms, and the subunit composition of a particular PP2A molecule determines its subcellular distribution and substrate specificity (reviewed in ref.2). One of the ways in which PP2A activity is regulated is through C-terminal methylation of the catalytic subunit (reviewed in refs. 8 and 9). Impaired methyl-donor metabolism is a risk factor for AD (10, 11), and PP2A dysregulation caused by impaired methylation is thought to be one of the molecular mechanisms contributing to this increased risk (12)(13)(14). Methylation promotes the formation of PP2A holoenzymes that contain Bα regulatory subunits (7,13,(15)(16)(17)(18)(19), and these forms of PP2A exhibit the greatest tau phosphatase activity (6, 7).PP2A m...

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“…Decreased phosphatase activity toward abnormally phosphorylated tau had been recognized in AD brains 59. Evidence for the mechanism of this decrease in phosphatase activity comes from the finding that LCMT‐1 is decreased in AD brains, associated with decreased levels of methylated PP2A, and closely matching tau pathology 17. In addition, levels of B α containing PP2A critical for regulating tau 60 are decreased in tangle‐bearing neurons correlating with increased tau pathology 18.…”

Section: Discussionmentioning

confidence: 99%

“…To enhance epitope antigenicity, samples were incubated in preheated sodium citrate (pH 6.0) for 30 min at 75°C. Sections were then blocked using 5% BSA for 1 h at room temperature and incubated overnight at 4°C with the following primary antibodies: antibody for LCMT‐1 (also known as PPMT) (1:100, a kind gift from Egon Ogris)17; 07‐095 for PME‐1 (1:500, Millipore); 6A3 for methylated‐PP2A (1:200, generated at Princeton University)4; 1D6 for demethylated‐PP2A (1:1000; Millipore)25; 06‐222 for total PP2A C subunit (1:500, Millipore); and 2G9 for total B55 α subunit of PP2A (1:500, Millipore). Sections were washed with PBS‐Tween (PBS‐T) three times and incubated with biotinylated secondary antibody for 1 h. After washing again with PBS‐T, sections were incubated with biotinylated HRP complex (Vector Laboratories, Burlingame, CA) for 1 h at room temperature, followed by incubation with 3,3′‐diaminobenzidine (DAB) for color development.…”

Section: Methodsmentioning

confidence: 99%

“…Abnormal regulation of PP2A has been noted in another neurodegenerative disorder, Alzheimer's disease (AD), with decreased phosphatase activity and reduced PP2A methylation in postmortem brains 17, 18. Furthermore, PP2A has been shown to be the major phosphatase acting on phospho‐tau,15 and EHT ameliorates the neurodegenerative phenotype in a rat model of AD 19…”

Section: Introductionmentioning

confidence: 99%

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Dysregulation of protein phosphatase 2A in parkinson disease and dementia with lewy bodies

Park

Lee

Park

et al. 2016

Ann Clin Transl Neurol

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ObjectiveProtein phosphatase 2A (PP2A) is a heterotrimeric holoenzyme composed of a catalytic C subunit, a structural A subunit, and one of several regulatory B subunits that confer substrate specificity. The assembly and activity of PP2A are regulated by reversible methylation of the C subunit. α‐Synuclein, which aggregates in Parkinson disease (PD) and dementia with Lewy bodies (DLB), is phosphorylated at Ser129, and PP2A containing a B55α subunit is a major phospho‐Ser129 phosphatase. The objective of this study was to investigate PP2A in α‐synucleinopathies.MethodsWe compared the state of PP2A methylation, as well as the expression of its methylating enzyme, leucine carboxyl methyltransferase (LCMT‐1), and demethylating enzyme, protein phosphatase methylesterase (PME‐1), in postmortem brains from PD and DLB cases as well as age‐matched Controls. Immunohistochemical studies and quantitative image analysis were employed.Results LCMT‐1 was significantly reduced in the substantia nigra (SN) and frontal cortex in both PD and DLB. PME‐1, on the other hand, was elevated in the PD SN. In concert with these changes, the ratio of methylated PP2A to demethylated PP2A was markedly decreased in PD and DLB brains in both SN and frontal cortex. No changes in total PP2A or total B55α subunit were detected.InterpretationThese findings support the hypothesis that PP2A dysregulation in α‐synucleinopathies may contribute to the accumulation of hyperphosphorylated α‐synuclein and to the disease process, raising the possibility that pharmacological means to enhance PP2A phosphatase activity may be a useful disease‐modifying therapeutic approach.

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

Cited by 182 publications

References 46 publications

PP2A holoenzyme assembly: in cauda venenum (the sting is in the tail)

PP2A holoenzyme assembly: in cauda venenum (the sting is in the tail)

PP2A methylation controls sensitivity and resistance to β-amyloid–induced cognitive and electrophysiological impairments

Dysregulation of protein phosphatase 2A in parkinson disease and dementia with lewy bodies

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