Highly Selective and Large Scale Mass Spectrometric Analysis of 4-Hydroxynonenal Modification via Fluorous Derivatization and Fluorous Solid-Phase Extraction

Yuan, Wenjuan; Zhang, Ying; Xiong, Yun; Tao, Tao; Wang, Yi; Yao, Jun; Zhang, Lei; Yan, Guoquan; Bao, Huimin; Lu, Haojie

doi:10.1021/acs.analchem.6b04850

Cited by 29 publications

(33 citation statements)

References 36 publications

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“…Chemicals-Alkynyl-ONE (aONE), 12 C and 13 C labeled azido-UVbiotin reagents (Azido-L-biotin and azido-H-biotin) were synthesized as described previously. ONE was purchased from Cayman (10185, Ann Arbor, MI).…”

Section: Methodsmentioning

confidence: 99%

Chemoproteomics Reveals Chemical Diversity and Dynamics of 4-Oxo-2-nonenal Modifications in Cells

Sun

Liu

et al. 2017

Molecular & Cellular Proteomics

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4-Oxo-2-nonenal (ONE) derived from lipid peroxidation modifies nucleophiles and transduces redox signaling by its reactions with proteins. However, the molecular interactions between ONE and complex proteomes and their dynamics remain largely unknown. Here we describe a quantitative chemoproteomic analysis of protein adduction by ONE in cells, in which the cellular target profile of ONE is mimicked by its alkynyl surrogate. The analyses reveal four types of ONE-derived modifications in cells, including ketoamide and Schiff-base adducts to lysine, Michael adducts to cysteine, and a novel pyrrole adduct to cysteine. ONE-derived adducts co-localize and exhibit crosstalk with many histone marks and redox sensitive sites. All four types of modifications derived from ONE can be reversed site-specifically in cells. Taken together, our study provides much-needed mechanistic insights into the cellular signaling and potential toxicities associated with this important lipid derived electrophile.

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Section: Methodsmentioning

confidence: 99%

Chemoproteomics Reveals Chemical Diversity and Dynamics of 4-Oxo-2-nonenal Modifications in Cells

Sun

Liu

et al. 2017

Molecular & Cellular Proteomics

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“…4a, Supplementary Figure 2a). To identify mechanisms directly affected by Gsta4/4-HNE, we analyzed RNA-seq data of corpus callosum-derived O4 + OLs to identify crucial molecules involved in these processes, using the following criteria: (1) significant differential expression (P ≤ 0.001) between DA Wt and DA Gsta4 (Supplementary Data 2); (2) the potential of the corresponding peptide to be modified by 4-HNE, as analyzed using high performance liquid chromatography screening 57,58 (Supplementary Data 3). There were 1042 upregulated mRNAs in DA Gsta4 OLs compared to in DA Wt in the naïve state, while only 105 mRNAs were downregulated (Fig.…”

Section: Gsta4 Leads To Expression Of Genes Involved In Ol Maturationmentioning

confidence: 99%

“…b Significant transcripts (gray) from RNA-seq of corpus callosum-derived O4 + OLs in naïve conditions. Transcripts corresponding to proteins potentially modified by 4-HNE (green) 57,58 . Heat-map indicates up (red) and down (blue) transcripts.…”

Section: Gsta4 Leads To Expression Of Genes Involved In Ol Maturationmentioning

confidence: 99%

Gsta4 controls apoptosis of differentiating adult oligodendrocytes during homeostasis and remyelination via the mitochondria-associated Fas-Casp8-Bid-axis

et al. 2020

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Arrest of oligodendrocyte (OL) differentiation and remyelination following myelin damage in multiple sclerosis (MS) is associated with neurodegeneration and clinical worsening. We show that Glutathione S-transferase 4α (Gsta4) is highly expressed during adult OL differentiation and that Gsta4 loss impairs differentiation into myelinating OLs in vitro. In addition, we identify Gsta4 as a target of both dimethyl fumarate, an existing MS therapy, and clemastine fumarate, a candidate remyelinating agent in MS. Overexpression of Gsta4 reduces expression of Fas and activity of the mitochondria-associated Casp8-Bid-axis in adult oligodendrocyte precursor cells, leading to improved OL survival during differentiation. The Gsta4 effect on apoptosis during adult OL differentiation was corroborated in vivo in both lysolecithin-induced demyelination and experimental autoimmune encephalomyelitis models, where Casp8 activity was reduced in Gsta4-overexpressing OLs. Our results identify Gsta4 as an intrinsic regulator of OL differentiation, survival and remyelination, as well as a potential target for future reparative MS therapies.

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“…Staining for 4-HNE in CC revealed the DA Gsta4 to have a reduced load of 4-HNE compared to DA Wt (Fig.3a, Fig.S2a). To identify transcripts potentially being directly affected by Gsta4/4-HNE we analyzed the RNA-seq data of CC derived O4 + OLs and used the following criteria to identify targets: significant differential expression (P=<0.001) between DA Wt and DA Gsta4 (Supplementary Table 2) and, the potential of the corresponding peptide to be modified by 4-8 HNE, proven by high performance liquid chromatography screening 59,60 (Supplementary Table 3). There were a 10-fold increase in transcripts being upregulated in DA Gsta4 OLs compared to DA Wt in naïve state ( Fig.3b left), however there was no difference in the proportion of transcripts of potentially 4-HNE modified peptides (Fig.3b green).…”

Section: Gsta4 Regulates Mitochondrial 4-hne Load In Olsmentioning

confidence: 99%

Gsta4 controls apoptosis of differentiating adult oligodendrocytes during homeostasis and remyelination via the mitochondria-associated Fas/Casp8/Bid-axis

Carlström

Zhu

Ewing

et al. 2020

Preprint

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Arrest of oligodendrocyte (OL) differentiation and remyelination following myelin damage in Multiple Sclerosis (MS) are associated with disease progression but the underlying mechanism are elusive. We show that Glutathione S-transferase 4α (Gsta4) is highly expressed during adult OL differentiation and that its loss prevents differentiation into myelinating OLs. Also, Gsta4 appeared to be a novel target for Clemastine, in clinical trial for MS. Over-expression of Gsta4 reduced the expression of Fas and activity along the 2 mitochondria-associated Casp8/Bid-axis in adult pre-OLs from the corpus callosum, together promoting enhanced pre-OL survival during differentiation. The Gsta4-mediated input on apoptosis during adult OL differentiation was further verified in the LPC and EAE model, where Casp8 were reduced in pre-OLs with high Gsta4 expression in an immune responseindependent fashion. Our results place Gsta4 as a key regulator of intrinsic mechanisms beneficial for OL differentiation and remyelination, and as a possible target for future MS therapies. IntroductionOligodendrocyte precursor cells (OPC) and oligodendrocytes (OL) are abundant throughout the central nervous system (CNS). They serve important roles in preserving the functionality and integrity of neuronal network connections, including providing metabolic support and enabling axonal signal transmission along myelinated fibers 1-4 . OLs are affected directly or indirectly in many CNS diseases, of which Multiple Sclerosis (MS) is one of the most widely studied 5 . Despite findings of proliferating OPCs around lesions 6,7 , OLs fail to remyelinate axons 8-12 which leads to neurodegeneration 9,13-15 .Previous studies have indicated that as many as 50% of pre-OLs undergo programmed cell death during development and 20-30% during post-natal conditions 16,17 . Recent studies have also shown mechanisms of OLs loss during development 18,19 , similar approached in postnatal animals and adult OLs are lacking.3 Remyelination do occur in adulthood 6,20-23 , but the time interval within which the OLs should receive crucial support in order to survive is restricted [24][25][26] .The OPCs capacity to remyelinate is strongly diminished over-time [27][28][29] and differentiating cells are exposed to considerable cellular stress [30][31][32][33] . Interestingly, mitochondrial function and the capacity to scavenge endogenous toxins are also diminished with ageing and diseaseprocesses such as those present in MS [34][35][36] . Notably, the activity of the primary sensor of cellular stress, Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), is also diminished with ageing 37,38 . Dysfunctional mitochondria and toxin scavenging induce lipid peroxidation (LPO) of unsaturated lipids in membranes, against which OLs are particularly vulnerable to [39][40][41][42] . Upon LPO, reactive aldehydes, such as 4-Hydroxynonenal (4-HNE), will be generated and diffuse in the cytosol, unless scavenged by conjugation to glutathione. If not scavenged, 4-HNE will bind to macro-molecules and...

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Highly Selective and Large Scale Mass Spectrometric Analysis of 4-Hydroxynonenal Modification via Fluorous Derivatization and Fluorous Solid-Phase Extraction

Cited by 29 publications

References 36 publications

Chemoproteomics Reveals Chemical Diversity and Dynamics of 4-Oxo-2-nonenal Modifications in Cells

Chemoproteomics Reveals Chemical Diversity and Dynamics of 4-Oxo-2-nonenal Modifications in Cells

Gsta4 controls apoptosis of differentiating adult oligodendrocytes during homeostasis and remyelination via the mitochondria-associated Fas-Casp8-Bid-axis

Gsta4 controls apoptosis of differentiating adult oligodendrocytes during homeostasis and remyelination via the mitochondria-associated Fas/Casp8/Bid-axis

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