Protein phosphatase 2A dysfunction in Alzheimer's disease

Abstract

Protein phosphatase 2A (PP2A) is a large family of enzymes that account for the majority of brain Ser/Thr phosphatase activity. While PP2A enzymes collectively modulate most cellular processes, sophisticated regulatory mechanisms are ultimately responsible for ensuring isoform-specific substrate specificity. Of particular interest to the Alzheimer's disease (AD) field, alterations in PP2A regulators and PP2A catalytic activity, subunit expression, methylation and/or phosphorylation, have been reported in AD-affected brain regions. "PP2A" dysfunction has been linked to tau hyperphosphorylation, amyloidogenesis and synaptic deficits that are pathological hallmarks of this neurodegenerative disorder. Deregulation of PP2A enzymes also affects the activity of many Ser/Thr protein kinases implicated in AD. This review will more specifically discuss the role of the PP2A/Bα holoenzyme and PP2A methylation in AD pathogenesis. The PP2A/Bα isoform binds to tau and is the primary tau phosphatase. Its deregulation correlates with increased tau phosphorylation in vivo and in AD. Disruption of PP2A/Bα-tau protein interactions likely contribute to tau deregulation in AD. Significantly, alterations in one-carbon metabolism that impair PP2A methylation are associated with increased risk for sporadic AD, and enhanced AD-like pathology in animal models. Experimental studies have linked deregulation of PP2A methylation with down-regulation of PP2A/Bα, enhanced phosphorylation of tau and amyloid precursor protein, tau mislocalization, microtubule destabilization and neuritic defects. While it remains unclear what are the primary events that underlie "PP2A" dysfunction in AD, deregulation of PP2A enzymes definitely affects key players in the pathogenic process. As such, there is growing interest in developing PP2A-centric therapies for AD, but this may be a daunting task without a better understanding of the regulation and function of specific PP2A enzymes.

Keywords: Alzheimer’s disease; LCMT1; amyloid; methylation; phosphorylation; protein phosphatase 2A; tau.

FIGURE 1

Schematic overview of the intricate regulation of PP2A enzymes. Major PP2A holoenzymes of this very large family (>96 enzymes) are heterotrimers containing a scaffolding “A” (one of two isoforms), a catalytic “C” (one of two isoforms), and one variable regulatory “B” subunit (one of twenty three isoforms). PP2A subunits are subjected to post-translational modifications, including methylation of the catalytic subunit on a conserved Leucine-309 residue, and phosphorylation. Endogenous subunit interactions, interaction of PP2A subunits with a variety of viral and cellular proteins, and binding of specific PP2A inhibitors and modulatory proteins to the catalytic subunit, all combine to modulate PP2A catalytic activity and ensure PP2A isoform-specific targeting and substrate specificity. Specific modulatory proteins also critically regulate PP2A biogenesis and stability. In addition, many compounds are known to enhance PP2A catalytic activity. See text for details.

FIGURE 2

Overview of PP2A dysfunction in AD and its link with the deregulation of tau. (A) Altered PP2A subunit expression, activity and post-translational modifications have been described in AD autopsy brain tissue. Some of these changes may be mediated by alterations in specific PP2A modulatory proteins (LCMT1, PTPA, alpha4) and endogenous PP2A inhibitors (I₁^PP2A and I₂^PP2A) that have also been reported in AD autopsy brain tissue. They also decrease the interaction of PP2A with tau. (B) The biogenesis of the PP2A/Bα holoenzyme, the primary Ser/Thr tau phosphatase in vivo, is believed to be controlled by Leu-309 methylation of PP2A catalytic subunit by LCMT1. This reaction requires the supply of SAM, the universal methyl donor, and is inhibited by SAH. The PP2A methylesterase, PME-1, can demethylate and inactivate PP2A through distinct mechanisms, and form a complex with inactive PP2A enzymes. Those inactive complexes could be-reactivated via the action of the PP2A activator PTPA, allowing for subsequent methylation of PP2A C subunit. Many brain Ser/Thr protein kinases, including GSK3β, oppose the action of PP2A/Bα and promote tau phosphorylation. Inhibition and/or down-regulation of PP2A can enhance tau phosphorylation directly by preventing its dephosphorylation, or indirectly by up-regulating tau kinases.

FIGURE 3

Deregulation of PP2A-tau protein–protein interactions in AD. (A) The PP2A/Bα holoenzyme can directly interact with three- or four-repeat human tau isoforms via a domain encompassing the microtubule-binding repeats (orange), resulting in tau dephosphorylation. A specific proline-rich motif (yellow) that contains the Thr231 phosphorylation site plays a critical role in modulating PP2A-tau protein–protein interactions. (B) PP2A-tau protein–protein interaction can be inhibited in vitro by: (1) Alterations in tau, including AD-like phosphorylation and FTDP-17 missense mutations; (2) decreased expression levels of PP2A methylation and PP2A/Bα in AD; (3) Fyn kinase and pseudophosphorylated RpTPPKSP peptides. Disruption of normal PP2A-tau interactions is predicted to affect tau phosphorylation state and function.

FIGURE 4

Model for the link between alterations in one-carbon metabolism, deregulation of PP2A methylation and AD-like pathology. Dietary B-vitamin deficiency, genetic polymorphisms in key enzymes that metabolize folate and homocysteine, drugs (e.g., the anti-folate drug, methotrexate), diseases (e.g., liver disease) and aging can all lead to impairment of one-carbon metabolism. In turn, alterations in the methylation cycle result in decreased LCMT1 activity and/or expression levels, and subsequent down-regulation of PP2A methylation and PP2A/Bα holoenzymes. This is associated with the accumulation of phosphorylated tau and APP proteins in vivo. Experiments in cultured cells and in vitro also link alterations in neuronal PP2A methylation with disruption of PP2A-tau protein–protein interactions, alterations in the subcellular targeting of PP2A and tau, APP processing, microtubule stability, and neuritic defects.