TY - JOUR
T1 - Dysregulation of protein phosphatase 2A in parkinson disease and dementia with lewy bodies
AU - Park, Hye Jin
AU - Lee, Kang Woo
AU - Park, Eun S.
AU - Oh, Stephanie
AU - Yan, Run
AU - Zhang, Jie
AU - Beach, Thomas G.
AU - Adler, Charles H.
AU - Voronkov, Michael
AU - Braithwaite, Steven P.
AU - Stock, Jeffry B.
AU - Mouradian, M. Maral
N1 - Funding Information: We are grateful to the Banner Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona, and the Arizona Parkinson Disease consortium for the clinical data and provision of human brain tissue samples. This study was supported by a grant from the Michael J. Fox Foundation for Parkinson's Research to S.P.B. and M.M.M. T.G.B. is supported by grants from the NIA, NINDS, Michael J. Fox Foundation and the State of Arizona. J.B.S. is supported by NIH grant AT006868. M.M.M. is the William Dow Lovett Professor of Neurology and is supported by the American Parkinson Disease Association and by NIH grants AT006868 and NS073994. The Banner Sun Health Research Institute Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson's Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer's Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson's Disease Consortium), and the Michael J. Fox Foundation for Parkinson's Research. Publisher Copyright: © 2016 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.
PY - 2016/10/1
Y1 - 2016/10/1
N2 - 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 Ser129, and PP2A containing a B55α subunit is a major phospho-Ser129 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.
AB - 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 Ser129, and PP2A containing a B55α subunit is a major phospho-Ser129 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.
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U2 - https://doi.org/10.1002/acn3.337
DO - https://doi.org/10.1002/acn3.337
M3 - Article
C2 - 27752512
VL - 3
SP - 769
EP - 780
JO - Annals of Clinical and Translational Neurology
JF - Annals of Clinical and Translational Neurology
SN - 2328-9503
IS - 10
ER -