PubMed: 24653673

Protein phosphatase 2A dysfunction in Alzheimer's disease.
Frontiers in molecular neuroscience
Sontag E | Sontag JM

Evidence 01f8338ad8

Like all methyltransferases,LCMT1 activity depends on the supply of the universal methyl donor, S-adenosylmethionine (SAM),and is inhibited by S-adenosylhomocysteine (SAH; Leulliot et al.,2004; Sontag et al.,2007).

Evidence a2cb596853

Conversely, many endogenous small molecules, comprising metal cations, ceramides and polyamines, can enhance the activity of PP2A enzymes (Reviewed in Voronkov et al.,2011).

Evidence cac00646c8

Natural toxins such as okadaic acid, calyculin ,and fostriecin (Reviewed in Swingle et al., 2007), and endogenous nuclear inhibitors called I1 PP2A and I2 PP2A/SET (Li and Damuni, 1998), can directly bind to the catalytic subunit and inhibit the phosphatase activity of the entire family of PP2A enzymes.

Evidence 41fe1bbd06

In vivo use of phosphatase inhibitors such as okadaic acid has been shown in many studies to induce cognitive impairment and widespread neurotoxic effects that are reminiscent of the hallmark pathological processes occurring in AD pathology, i.e., the accumulation of P-tau, amyloidogenesis, synapse loss and neurodegeneration (Malchiodi-Albedi et al., 1997; Arendt et al., 1998; Sun et al.,2003; Kamat et al.,2013)

Evidence 8ba872d0d0

Dietary folate and B-vitamin deficiency (Sontag et al.,2008; Nicolia et al.,2010) and elevated homocysteine levels (Sontag et al.,2007, 2013; Zhang et al.,2008) lead to down-regulation of PP2A methylation and concomitant phosphorylation of tau and/or APP in vivo

Evidence 17e886549b

Apart from affecting tau phosphorylation, abnormal activation of GSK3β, cdk5, and ERK has been linked to cytoskeletal abnormalities (microtubules, neurofilaments), alterations in amyloid precursor protein (APP) phosphorylation and processing, impairment of neurogenesis, alterations in synaptic plasticity and induction of apoptotic processes (Reviewed in Crews and Masliah, 2010; Medina and Avila, 2013, 2014).

Evidence 31032b5788

Lastly, increased phosphorylation of PP2A at Tyr-307 has been found in P-tau-rich, tangle-bearing neurons from post-mortem brain (Liu et al.,2008b).

Evidence e7910d74c5

PP2A enzymes can also associate with protein kinases that have been linked to AD, such as glycogen synthase kinase 3β (GSK3β) and cyclin-dependent kinase 5 (cdk5; Plattner et al.,2006), and neuronal receptors, e.g., the NMDA receptor (Chan and Sucher, 2001) and the metabotropic glutamate receptor 5 (Mao et al., 2005; Arif et al., 2014).

Evidence 6e5dd87a77

PP2A enzymes can also become transiently inactivated following tyrosine phosphorylation of the catalytic subunit at the putative Tyr-307 site,via activation of src kinase, epidermal growth factor receptor or insulin signaling (Chen et al.,1992).

Evidence 3d947e23e2

The deregulation of PP2A methylation in AD is especially interesting, not only because it can lead to a loss of PP2A/Bα, a major tau regulator, but also because PP2A methylation state is intimately linked to the integrity of one-carbon metabolism, which regulates SAM supply (Reviewed in Fowler,2005).

Evidence 3da7ab127c

Remarkably, impairment of one-carbon metabolism in animal models can reproduce AD-like pathological features: accumulation of P-tau (Sontag et al.,2007; Zhang et al.,2008; Wei et al.,2011); enhanced amyloidogenesis (Pacheco-Quinto et al.,2006; Zhang et al.,2009; Zhuo et al.,2010; Zhuo and Pratico,2010); increased phosphorylation of APP at the regulatory Thr-668 site (Sontag et al.,2007; Zhang et al.,2009); increased sensitivity to amyloid toxicity (Kruman et al.,2002); and cognitive impairment (Bernardo et al.,2007; Wei et al.,2011; Rhodehouse et al., 2013).

Evidence 2e4e71d781

For instance, the Bα subunit specifically and markedly facilitates dephosphory- lation of tau by PP2A (Sontag et al.,1996; Xu et al.,2008).

Evidence eb373ea99d

Besides Ser/Thr kinases, the protein tyrosine kinase src promotes the phosphorylation of PP2A on Tyr-307, resulting in PP2A inactivation and subsequent tau phosphorylation (Xiong et al.,2013; Arif et al.,2014).

Evidence fa426c4e17

While many PP2A holoenzymes have the potential to indirectly affect tau phosphorylation by modulating key tau protein kinases (For example see Louis et al., 2011), biochemical and structural studies have demonstrated that PP2A/Bα is the primary PP2A isoform that mediates tau dephosphorylation (Sontag et al.,1996, 1999; Xu et al.,2008).

Evidence ac190ca450

For example, PME-1 stabilizes a nuclear pool of inactive PP2A enzymes (Longin et al., 2008), while methylation by LCMT1 influences the amounts of PP2A enzymes bound to plasma membrane microdomains (Sontag et al.,2013).

Evidence 95b1768c68

There is a significant decrease in total PP2A activity measured in AD cortical and hippocampal brain homogenates (Gong et al.,1993; Gong et al.,1995; Sontag et al.,2004b).

Evidence 47529f9231

In contrast, “PP2A” expression levels are increased in AD astrocytes (Pei et al., 1997).

Evidence c08aea4bbd

Collectively, those studies point to a central role for PP2A dysfunction in AD pathogenesis

Evidence 20e0110d4b

Deficits in PP2A activity are in line with the reported down-regulation of PP2A catalytic C subunit at the gene (Loring et al.,2001), mRNA (Vogelsberg-Ragaglia et al.,2001) and protein (Sontag et al.,2004b) expression levels in AD.

Evidence 9a0bd39371

Up-regulation of I1 PP2A and I2 PP2A, and mislocalization and cleavage of I2 PP2A, could underlie the inactivation of PP2A in AD neocortical neurons (Tanimukai et al.,2005).

Evidence ea6bbf9638

For instance, activated GSK3β has been reported to induce PP2A inactivation via several mechanisms: phosphorylation of PP2A on Tyr307 (Yao et al.,2011); demethylation of PP2A on Leu309 through inhibition of LCMT1 and up-regulation of PME1 (Yao et al.,2012); and accumulation of I2 PP2A (Liu et al.,2008a).

Evidence 8199da2ef5

Decreased expression levels of PTPA in AD brain tissue may also lead to inactivation of PP2A by indirectly increasing levels of PP2A phosphorylated at the Tyr-307 site (Luo et al.,2013).

Evidence 82859fc8e4

Not surprisingly, inhibition of total cellular PP2A activity ultimately leads to neuronal cell death.

Evidence e8a197394d

Specific PP2A inhibition has been proven to lead to in vivo deregulation of many major brain Ser/Thr kinases implicated in AD, including GSK3β (Wang et al., 2010; Louis et al., 2011), cdk5 (Louis et al., 2011; Kimura et al., 2013), extracellular signal- regulated kinase (ERK) and JNK (Kins et al., 2003).

Evidence bbe1f116af

Lastly, increased calpain-mediated cleavage of alpha4, which critically modulates PP2A stability, could be responsible for increased degradation of PP2A catalytic subunit in AD (Watkins et al., 2012).

Evidence c806c33946

Knock-down of PP2A catalytic subunit (Kins et al.,2001) or PP2A B’δ (or PPP2R5D) regulatory subunit (Louis et al.,2011), and expression of the methylation-site L309A C subunit mutant (Schild et al.,2006) all induce AD-like tau phosphorylation in transgenic mice

Evidence d0edbf67f7

Conversely, decreased PP2A methylation and PP2A/Bα levels in AD will disrupt normal PP2A-tau interactions (Sontag et al., 2007), thereby preventing PP2A-mediated tau dephosphorylation while allowing for enhanced binding of Fyn kinase or other regulators to the tau proteins.

Evidence 2574a6c607

Furthermore, direct interaction of PP2A catalytic subunit with specific regulatory proteins, including PME-1, LCMT1, the alpha4 subunit, and the PP2A phosphatase activator PTPA, critically modulates PP2A biogenesis and stability

Evidence 7592d461f8

Proteinphosphatase 2A catalytic subunit is uniquely methylated on Leu-309 by the dedicated leucine carboxyl methyltransferase-1 (LCMT-1; Lee et al.,1996; De Baere et al.,1999).

Evidence 88af2edaf9

Significantly, downregulation of LCMT1 expression leads to a significant decrease of PP2A methylation and concomitant loss of PP2A holoenzymes containing the regulatory Bα (or PPP2R2A) subunit (PP2A/Bα; Lee and Pallas,2007; Sontag et al.,2008; MacKay et al.,2013).

Evidence 7030f32018

Significantly, down-regulation of LCMT1 protein expression parallels the deficits in PP2A methylation observed in AD (Sontag et al.,2004a).

Evidence 92dad743e2

It is noteworthy that PP2A/Bα can directly bind to tau via a domain encompassing the microtubule-binding of tau; this interaction maximizes the efficiency of tau dephosphorylation by PP2A (Sontag et al.,1999; Xu et al.,2008; Figure 3A).

Evidence 8d73478a75

For instance, some B’ subunits target PP2A to the nucleus (McCright et al., 1996) or the centrosome (Flegg et al.,2010); Bα subunits can direct some PP2A pools to microtubules, which could serve as a cytoskeletal reservoir of inac- tive enzymes (Sontag et al.,1995; Hiraga and Tamura,2000).

Evidence 265cb8d229

More specifically, decreased expression levels of PP2A regulatory Bγ (or PPP2R2C) and B’ε (or PPP2R5E) subunit mRNAs in the hippocampus (Vogelsberg-Ragaglia et al.,2001), and cortical Bα subunit (Sontag et al.,2004b) have been reported in AD.

Evidence 64507e4b37

Conversely, the PP2A-specific methylesterase PME-1 can directly bind to the active site of the catalytic subunit, remove the methyl group and inactivate PP2A by evicting manganese ions required for phosphatase activity (Xing et al.,2008).

Evidence 21099827c7

Of particular relevance to the Alzheimer’s disease (AD) field, PP2A/Bα holoenzymes can directly bind to the microtubule-associated protein tau (Sontag et al.,1999, 2012; Xu et al.,2008).

Evidence a16b445cf3

Notably, the loss of neuronal PP2A/Bα holoenzymes correlates with the down-regulation of PP2A methylation and severity of phosphorylated tau (P-tau) pathology in AD-affected brain regions (Sontag et al.,2004 a,b).

Evidence 1d363f7fb6

As described earlier, it is especially significant that the biogenesis of PP2A/Bα holoenzymes is intimately related to the methylation state of PP2A

Evidence 1dd387e30d

Specific inhibition of PP2A/Bα is associated with enhanced tau phosphorylation at many AD-like phospho epitopes, and subsequent inability of tau to bind to and stabilize microtubules (Sontag et al., 1996).

Evidence f163e3b328

Deregulation of PP2A/Bα alone also affects microtubule stability (Nunbhakdi-Craig et al., 2007) and neurite outgrowth (Sontag et al.,2010) in neuroblastoma cells

Evidence 6863844948

Adding another layer of complexity to the regulation of PP2A holoenzymes, protein kinase A-mediated serine phosphorylation of selective PPP2R5A and PPP2R5D regulatory subunits belonging to the B’family can also modulate PP2A catalytic activity (Ahn et al.,2007; Kirchhefer et al.,2014).

Evidence 382e018206

In cultured cells, deregulation of PP2A methylation also affects APP processing (Sontag et al.,2007), neurite outgrowth (Sontag et al.,2010) and tau distribution (Sontag et al.,2013).

Evidence 12880bd5d3

Notably, tau missense mutations found in frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17; Goedert et al.,2000) and AD-mimicking tau phosphorylation in proline-rich motifs (Eidenmuller et al.,2001) inhibit the association of tau with PP2A (Figure3B).

Evidence 798755080b

Phosphorylation of the Thr-231 residue in this motif markedly decreases the affinity of tau for PP2A.

Evidence aaaafb0da8

This is potentially physiologically significant since phosphorylation of tau at Thr-231, a target site for ERK2, GSK3β, and cdk5, occurs early in AD and can further inhibit the ability of PP2A/Bα to dephosphorylate other major AD-tau phosphoepitopes (Landrieu et al.,2011).

Evidence d7aab79651

Other modifications of PP2AC subunit include ubiquitination, which targets PP2A for degradation (McConnelletal.,2010), and tyrosine nitration that increases PP2A activity in endothelial cells (Wu and Wilson, 2009).

Evidence d3b5b19c60

Methylation is thought to play a critical role in the biogenesis of PP2A holoenzymes.

Evidence e650d877cc

A recent report also indicates the existence of regulated phosphorylation of the scaffolding A subunit on Ser/Thr residues, which affects its binding to the catalytic subunit and PP2A signaling in the heart (Kotlo et al.,2014).

Evidence 0013f2c550

Moreover, expression of an I2 PP2A fragment can recapitulate AD-like pathology in rat brain (Wang et al.,2010).


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