Protein phosphatase 2A dysfunction in Alzheimerâ€™s disease

Jean-Marie Sontag,Estelle Sontag

doi:10.3389/fnmol.2014.00016

Jean-Marie Sontag, Estelle Sontag

Open Access

https://doi.org/10.3389/fnmol.2014.00016

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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.

Highlights

Protein phosphatase 2A (PP2A) is a large family of enzymes that account for the majority of brain Ser/Thr phosphatase activity
THE MIND-BLOWING SOPHISTICATION OF “PP2A” REGULATION Protein phosphatase 2A regulation is highly complex, involving the interplay of specific regulatory subunits and modulators, and post-translational modifications, protein–protein interactions and subcellular compartmentalization (Figure 1). These interwoven regulatory processes coalesce to ensure PP2A isoform-specific functional specificity, as described below: PP2A POST-TRANSLATIONAL MODIFICATIONS Protein phosphatase 2A catalytic subunit is uniquely methylated on Leu-309 by the dedicated leucine carboxyl methyltransferase1 (LCMT-1; Lee et al, 1996; De Baere et al, 1999)
A recent report 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)

Summary

Introduction

Protein phosphatase 2A (PP2A) is a large family of enzymes that account for the majority of brain Ser/Thr phosphatase activity. 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 modulate PP2A catalytic activity (Ahn et al, 2007; Kirchhefer et al, 2014). 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.

Results

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