%0 Journal Article
%T Protein phosphatase 2A dysfunction in Alzheimer¡¯s disease
%A Jean-Marie Sontag
%A Estelle Sontag
%J Frontiers in Molecular Neuroscience
%D 2014
%I Frontiers Media
%R 10.3389/fnmol.2014.00016
%X 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/B¦Á holoenzyme and PP2A methylation in AD pathogenesis. The PP2A/B¦Á 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/B¦Á-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/B¦Á, 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.
%K Alzheimer¡¯s disease
%K amyloid
%K LCMT1
%K methylation
%K phosphorylation
%K protein phosphatase 2A
%K tau
%U http://www.frontiersin.org/Journal/10.3389/fnmol.2014.00016/abstract