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Dysregulation of protein phosphatase 2A in parkinson disease and dementia with lewy bodies
OBJECTIVE: Protein phosphatase 2A (PP2A) 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 PP2A are regulated by reversible methylation of the C subunit. α...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5048387/ https://www.ncbi.nlm.nih.gov/pubmed/27752512 http://dx.doi.org/10.1002/acn3.337 |
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author | Park, Hye‐Jin Lee, Kang‐Woo 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 |
author_facet | Park, Hye‐Jin Lee, Kang‐Woo 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 |
author_sort | Park, Hye‐Jin |
collection | PubMed |
description | OBJECTIVE: Protein phosphatase 2A (PP2A) 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 PP2A 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 PP2A containing a B55α subunit is a major phospho‐Ser(129) phosphatase. The objective of this study was to investigate PP2A in α‐synucleinopathies. METHODS: We compared the state of PP2A 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 PP2A to demethylated PP2A was markedly decreased in PD and DLB brains in both SN and frontal cortex. No changes in total PP2A or total B55α subunit were detected. INTERPRETATION: These findings support the hypothesis that PP2A 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 PP2A phosphatase activity may be a useful disease‐modifying therapeutic approach. |
format | Online Article Text |
id | pubmed-5048387 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-50483872016-10-17 Dysregulation of protein phosphatase 2A in parkinson disease and dementia with lewy bodies Park, Hye‐Jin Lee, Kang‐Woo 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 Ann Clin Transl Neurol Research Articles OBJECTIVE: Protein phosphatase 2A (PP2A) 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 PP2A 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 PP2A containing a B55α subunit is a major phospho‐Ser(129) phosphatase. The objective of this study was to investigate PP2A in α‐synucleinopathies. METHODS: We compared the state of PP2A 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 PP2A to demethylated PP2A was markedly decreased in PD and DLB brains in both SN and frontal cortex. No changes in total PP2A or total B55α subunit were detected. INTERPRETATION: These findings support the hypothesis that PP2A 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 PP2A phosphatase activity may be a useful disease‐modifying therapeutic approach. John Wiley and Sons Inc. 2016-09-07 /pmc/articles/PMC5048387/ /pubmed/27752512 http://dx.doi.org/10.1002/acn3.337 Text en © 2016 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs (http://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Research Articles Park, Hye‐Jin Lee, Kang‐Woo 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 Dysregulation of protein phosphatase 2A in parkinson disease and dementia with lewy bodies |
title | Dysregulation of protein phosphatase 2A in parkinson disease and dementia with lewy bodies |
title_full | Dysregulation of protein phosphatase 2A in parkinson disease and dementia with lewy bodies |
title_fullStr | Dysregulation of protein phosphatase 2A in parkinson disease and dementia with lewy bodies |
title_full_unstemmed | Dysregulation of protein phosphatase 2A in parkinson disease and dementia with lewy bodies |
title_short | Dysregulation of protein phosphatase 2A in parkinson disease and dementia with lewy bodies |
title_sort | dysregulation of protein phosphatase 2a in parkinson disease and dementia with lewy bodies |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5048387/ https://www.ncbi.nlm.nih.gov/pubmed/27752512 http://dx.doi.org/10.1002/acn3.337 |
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