title: Dysregulation of protein phosphatase 2A in parkinson disease and dementia with lewy bodies.
abstract: 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 B55αsubunit is a major phospho-Ser129phosphatase. The objective of this study was to investigate PP2A inα-synucleinopathies.
  
  
  
  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.
  
  
  
  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 B55αsubunit were detected.
  
  
  
  These findings support the hypothesis that PP2A dysregulation inα-synucleinopathies may contribute to the accumulation of hyperphosphorylatedα-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.
authors.affiliation: Center for Neurodegenerative and Neuroimmunologic Diseases Department of Neurology Rutgers - Robert Wood Johnson Medical School Piscataway New Jersey 08854.
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: Park
authors.affiliation: Center for Neurodegenerative and Neuroimmunologic Diseases Department of Neurology Rutgers - Robert Wood Johnson Medical School Piscataway New Jersey 08854; Present address: Department of Biological Sciences Korea Advanced Institute of Science and Technology (KAIST) Daejeon 305-701 Republic of Korea.
authors.forename: Kang-Woo
authors.initials: KW
authors.lastname: Lee
authors.affiliation: Center for Neurodegenerative and Neuroimmunologic Diseases Department of Neurology Rutgers - Robert Wood Johnson Medical School Piscataway New Jersey 08854; Present address: Albert Einstein College of Medicine Bronx New Jersey 10461.
authors.forename: Eun S
authors.initials: ES
authors.lastname: Park
authors.affiliation: Center for Neurodegenerative and Neuroimmunologic Diseases Department of Neurology Rutgers - Robert Wood Johnson Medical School Piscataway New Jersey 08854.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Oh
authors.affiliation: Center for Neurodegenerative and Neuroimmunologic Diseases Department of Neurology Rutgers - Robert Wood Johnson Medical School Piscataway New Jersey 08854.
authors.forename: Run
authors.initials: R
authors.lastname: Yan
authors.affiliation: Center for Neurodegenerative and Neuroimmunologic Diseases Department of Neurology Rutgers - Robert Wood Johnson Medical School Piscataway New Jersey 08854.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Banner Sun Health Research Institute Sun City Arizona 85372.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Beach
authors.affiliation: Mayo Clinic Scottsdale Arizona 85259.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Adler
authors.affiliation: Signum Biosciences 133 Wall Street Princeton New Jersey 08540.
authors.forename: Michael
authors.initials: M
authors.lastname: Voronkov
authors.affiliation: Signum Biosciences133 Wall Street Princeton New Jersey 08540; Present address: Alkahest 75 Shoreway Drive, Suite D San Carlos California 94070.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Braithwaite
authors.affiliation: Signum Biosciences133 Wall Street Princeton New Jersey 08540; Department of Molecular Biology Princeton University Princeton New Jersey 08544.
authors.forename: Jeffry B
authors.initials: JB
authors.lastname: Stock
authors.affiliation: Center for Neurodegenerative and Neuroimmunologic Diseases Department of Neurology Rutgers - Robert Wood Johnson Medical School Piscataway New Jersey 08854.
authors.forename: M Maral
authors.initials: MM
authors.lastname: Mouradian