Phenylarsine Oxide Binding Reveals Redox-Active and Potential Regulatory Vicinal Thiols on the Catalytic Subunit of Protein Phosphatase 2A

Foley, Timothy D.; Melideo, Scott L.; Healey, Adriana E.; Lucas, Eugene J.; Koval, Jason A.

doi:10.1007/s11064-010-0310-4

Cited by 26 publications

(15 citation statements)

References 31 publications

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“…Most of these proteins, including DPYL2, RhoGDI, CapZ beta, PP2A-alpha, UCHL1, HSC71 and enolase, are prone to oxidative modifications. [60][61][62][63] If anatomical alterations clearly indicate damage caused by oxidative stress in neuronal circuits, they are not necessarily causally linked to behavioral alterations, although they may contribute to them. 64 Although oxidative stress are mostly in neurons, there were also indications of oxidative stress in some glial cells in V animals.…”

Section: Upstream Regulation Of Nrf2mentioning

confidence: 99%

Nrf2-dependent persistent oxidative stress results in stress-induced vulnerability to depression

et al. 2016

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Stressful life events produce a state of vulnerability to depression in some individuals. The mechanisms that contribute to vulnerability to depression remain poorly understood. A rat model of intense stress (social defeat (SD), first hit) produced vulnerability to depression in 40% of animals. Only vulnerable animals developed a depression-like phenotype after a second stressful hit (chronic mild stress). We found that this vulnerability to depression resulted from a persistent state of oxidative stress, which was reversed by treatment with antioxidants. This persistent state of oxidative stress was due to low brain-derived neurotrophic factor (BDNF) levels, which characterized the vulnerable animals. We found that BDNF constitutively controlled the nuclear translocation of the master redox-sensitive transcription factor Nrf2, which activates antioxidant defenses. Low BDNF levels in vulnerable animals prevented Nrf2 translocation and consequently prevented the activation of detoxifying/antioxidant enzymes, ultimately resulting in the generation of sustained oxidative stress. Activating Nrf2 translocation restored redox homeostasis and reversed vulnerability to depression. This mechanism was confirmed in Nrf2-null mice. The mice displayed high levels of oxidative stress and were inherently vulnerable to depression, but this phenotype was reversed by treatment with antioxidants. Our data reveal a novel role for BDNF in controlling redox homeostasis and provide a mechanistic explanation for post-stress vulnerability to depression while suggesting ways to reverse it. Because numerous enzymatic reactions produce reactive oxygen species that must then be cleared, the finding that BDNF controls endogenous redox homeostasis opens new avenues for investigation.

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Section: Upstream Regulation Of Nrf2mentioning

confidence: 99%

Nrf2-dependent persistent oxidative stress results in stress-induced vulnerability to depression

et al. 2016

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“…For comparison, only 4-6% of total proteins from whole brains were found to contain disulfide bonds under these (Foley et al, unpublished observation) and comparable conditions (Foley et al 2010(Foley et al , 2011. Furthermore, it is important to note that our previous findings that the extracellular protein albumin, which contains 17 disulfide bonds, is one of two proteins found to be highly enriched among the disulfide bond-containing proteins argues that the fraction of intracellular proteins exhibiting intrachain disulfide bonds in vivo is likely to be substantially lower than the 4-6% value (Foley et al 2010).…”

Section: Discussionmentioning

confidence: 94%

“…2), may undergo reversible oxidation to form disulfide bonds was examined following preparation of these fractions in the absence of reducing agents and subsequent alkylation of reduced protein thiols with iodoacetamide. We have shown previously that the omission of reducing agents is sufficient to promote disulfide bond formation in proteins during subcellular fractionation procedures even when carried out 4°C and in the presence of 1 mM EDTA (Foley et al 2011).…”

Section: Snap-25 Forms Intrachain Disulfide Bondsmentioning

confidence: 99%

SNAP-25 Contains Non-Acylated Thiol Pairs that can Form Intrachain Disulfide Bonds: Possible Sites for Redox Modulation of Neurotransmission

et al. 2011

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Intrachain disulfide bond formation among the cysteine thiols of SNAP-25, a component of the SNARE protein complex required for neurotransmitter release, has been hypothesized to link oxidative stress and inhibition of synaptic transmission. However, neither the availability in vivo of SNAP-25 thiols, which are known targets of S-palmitoylation, nor the tendency of these thiols to form intrachain disulfide bonds is known. We have examined, in rat brain extracts, both the availability of closely spaced, or vicinal, thiol pairs in SNAP-25 and the propensity of these dithiols toward disulfide bond formation using a method improved by us recently that exploits the high chemoselectivity of phenylarsine oxide (PAO) for vicinal thiols. The results show for the first time that a substantial fraction of soluble and, to a lesser extent, particulate SNAP-25 contain non-acylated PAO-binding thiol pairs and that these thiols in soluble SNAP-25 in particular have a high propensity toward disulfide bond formation. Indeed, disulfide bonds were detected in a small fraction of soluble SNAP-25 even under conditions designed to prevent or greatly limit protein thiol oxidation during experimental procedures. These results provide direct experimental support for the availability, in a subpopulation of SNAP-25, of vicinal thiols that may confer on one or more isoforms of this family of proteins a sensitivity to oxidative stress.

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“…Evidence has also been reported that PP2A phosphatase activity is sensitive to oxidative stress,42 and this sensitivity is proposed to be mediated by oxidation of a pair of vicinal cysteines located near the phosphatase active site of the C subunit 43. Additionally, PP2A oxidation by exposure to micromolar levels of hydrogen peroxide has been shown to completely block its methylation by LCMT‐1 44.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of protein phosphatase 2A in parkinson disease and dementia with lewy bodies

Park

Lee

Park

et al. 2016

Ann Clin Transl Neurol

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ObjectiveProtein 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.MethodsWe 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.InterpretationThese 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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Phenylarsine Oxide Binding Reveals Redox-Active and Potential Regulatory Vicinal Thiols on the Catalytic Subunit of Protein Phosphatase 2A

Cited by 26 publications

References 31 publications

Nrf2-dependent persistent oxidative stress results in stress-induced vulnerability to depression

Nrf2-dependent persistent oxidative stress results in stress-induced vulnerability to depression

SNAP-25 Contains Non-Acylated Thiol Pairs that can Form Intrachain Disulfide Bonds: Possible Sites for Redox Modulation of Neurotransmission

Dysregulation of protein phosphatase 2A in parkinson disease and dementia with lewy bodies

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