Open AccessDysregulation of protein phosphatase 2A in parkinson disease and dementia with lewy bodies
Author(s) -
Park HyeJin,
Lee KangWoo,
Park Eun S.,
Oh Stephanie,
Yan Run,
Zhang Jie,
Beach Thomas G.,
Adler Charles H.,
Voronkov Michael,
Braithwaite Steven P.,
Stock Jeffry B.,
Mouradian M. Maral
Publication year - 2016
Publication title -
annals of clinical and translational neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.824
H-Index - 42
ISSN - 2328-9503
DOI - 10.1002/acn3.337
Subject(s) - dementia with lewy bodies , synucleinopathies , protein subunit , protein phosphatase 2 , parkinson's disease , phosphatase , alpha synuclein , substantia nigra , medicine , phosphorylation , microbiology and biotechnology , biochemistry , biology , dementia , disease , gene
Objective Protein phosphatase 2A ( PP 2A) 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 PP 2A 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 Ser 129 , and PP 2A containing a B55 α subunit is a major phospho‐Ser 129 phosphatase. The objective of this study was to investigate PP 2A in α ‐synucleinopathies. Methods We compared the state of PP 2A 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 PP 2A to demethylated PP 2A was markedly decreased in PD and DLB brains in both SN and frontal cortex. No changes in total PP 2A or total B55 α subunit were detected. Interpretation These findings support the hypothesis that PP 2A 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 PP 2A phosphatase activity may be a useful disease‐modifying therapeutic approach.