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S-Nitrosylation-mediated dysfunction of TCA cycle enzymes in synucleinopathy studied in postmortem human brains and hiPSC-derived neurons

ABSTRACT: Here, we used a method, SNO trapping by triaryl phosphine (SNOTRAP), combined with mass spectrometry, to identify SNO-proteins present in post-mortem brain samples. Following analysis of SNO-proteins in samples of 11 human brains from patients LBD and controls, we detected 943 SNO-proteins and 1,552 SNO-sites, covering a wide range of the SNO proteome.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

SUBMITTER: Hongmei Yang

LAB HEAD: Hongmei Yang

PROVIDER: PXD036703 | Pride | 2024-10-17

REPOSITORIES: Pride

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S-Nitrosylation-mediated dysfunction of TCA cycle enzymes in synucleinopathy studied in postmortem human brains and hiPSC-derived neurons.

Doulias Paschalis-Thomas PT Yang Hongmei H Andreyev Alexander Y AY Dolatabadi Nima N Scott Henry H K Raspur Charlene C Patel Parth R PR Nakamura Tomohiro T Tannenbaum Steven R SR Ischiropoulos Harry H Lipton Stuart A SA

Cell chemical biology 20230720 8

A causal relationship between mitochondrial metabolic dysfunction and neurodegeneration has been implicated in synucleinopathies, including Parkinson disease (PD) and Lewy body dementia (LBD), but underlying mechanisms are not fully understood. Here, using human induced pluripotent stem cell (hiPSC)-derived neurons with mutation in the gene encoding α-synuclein (αSyn), we report the presence of aberrantly S-nitrosylated proteins, including tricarboxylic acid (TCA) cycle enzymes, resulting in act ...[more]

PMID: 37478858

Similar Datasets

S-Nitrosylation-mediated dysfunction of TCA cycle enzymes in synucleinopathy studied in postmortem human brains and hiPSC-derived neurons

Project description:A causal relationship between mitochondrial metabolic dysfunction and neurodegeneration has been strongly implicated in synucleinopathies, including Parkinson’s disease (PD) and Lewy body dementia (LBD), but the underlying molecular basis is not fully understood. Here, using human induced pluripotent stem cell (hiPSC)-derived neurons bearing a pathological point mutation in the gene encoding α-synuclein (αSyn) protein, we report that the presence of many aberrantly S-nitrosylated proteins, including multiple tricarboxylic acid (TCA) cycle enzymes, which results in inhibition of their activity, as assessed by carbon-labeled metabolic flux experiments. The block in the TCA cycle principally affects the step at -ketoglutarate dehydrogenase/succinyl coenzyme-A synthetase, metabolizing -ketoglutarate to succinate. Notably, human LBD brain manifests a similar pattern of aberrantly S-nitrosylated TCA enzymes, indicating the pathophysiological relevance of these results. Inhibition of mitochondrial energy metabolism in neurons is known to compromise dendritic length and synaptic integrity, eventually leading to neuronal cell death, with consequent neurodegenerative phenotypes. Our new evidence indicates that redox-mediated inhibition of the TCA cycle via aberrant protein S-nitrosylation contributes to this bioenergetic failure.

2024-10-17 | PXD036797 | Pride

S-nitrosation of proteins relevant to Alzheimer’s disease during early stages of neurodegeneration

Project description:Protein S-nitrosation (SNO-protein) is a post-translational modification in which a cysteine (Cys) residue is modified by nitric oxide (SNO-Cys). SNO-proteins impact many biological systems, but their identification has been technically challenging. We developed a chemical proteomic strategy - SNOTRAP (SNO trapping by triaryl phosphine) -that allows improved identification of SNO-proteins by mass spectrometry. We found that S-nitrosation is elevated during early stages of neurodegeneration, preceding cognitive decline. We identified changes in the SNOproteome during early neurodegeneration that are potentially relevant for synapse function, metabolism, and Alzheimer’s disease pathology. SNO-proteome analysis further reveals a potential linear motif for SNO-Cys sites that are altered during neurodegeneration. Our strategy can be applied to multiple cellular and disease contexts and can reveal signaling networks that aid drug development.

2016-03-31 | PXD003802 | Pride

S-Nitrosylation-mediated dysfunction of TCA cycle enzymes in synucleinopathy studied in postmortem human brains and hiPSC-derived neurons.

Project description:A causal relationship between mitochondrial metabolic dysfunction and neurodegeneration has been implicated in synucleinopathies, including Parkinson disease (PD) and Lewy body dementia (LBD), but underlying mechanisms are not fully understood. Here, using human induced pluripotent stem cell (hiPSC)-derived neurons with mutation in the gene encoding α-synuclein (αSyn), we report the presence of aberrantly S-nitrosylated proteins, including tricarboxylic acid (TCA) cycle enzymes, resulting in activity inhibition assessed by carbon-labeled metabolic flux experiments. This inhibition principally affects α-ketoglutarate dehydrogenase/succinyl coenzyme-A synthetase, metabolizing α-ketoglutarate to succinate. Notably, human LBD brain manifests a similar pattern of aberrantly S-nitrosylated TCA enzymes, indicating the pathophysiological relevance of these results. Inhibition of mitochondrial energy metabolism in neurons is known to compromise dendritic length and synaptic integrity, eventually leading to neuronal cell death. Our evidence indicates that aberrant S-nitrosylation of TCA cycle enzymes contributes to this bioenergetic failure.

| S-EPMC10530441 | biostudies-literature

Alzheimer’s Disease (AD) and Lewy Body Dementia (LBD): Detection of S-Nitrosylation in Key Proteins in Human, Post-mortem Brain Samples

Project description:FAD and Lewy Body Dementia (LBD): Detection of S-Nitrosylation in Key Proteins in Human, Post-mortem Brain Samples

2023-03-10 | PXD020945 | Pride

Metabolic bypass partially rescues S-nitrosylation-induced TCA cycle inhibition and synapse loss in Alzheimer’s disease human neurons

Project description:In Alzheimer’s disease (AD), dysfunctional mitochondrial metabolism has been associated with synaptic loss, the major pathological correlate of cognitive decline. Mechanistic insight for this relationship, however, is still lacking. Here, comparing isogenic wild-type and AD mutant human induced pluripotent stem cell (hiPSC)-derived cerebrocortical neurons (hiN), we found evidence for compromised mitochondrial energy production in AD using the Seahorse platform to analyze glycolysis and oxidative phosphorylation (OXPHOS). By isotope-labeled metabolic flux experiments, a major block in activity occurred in the tricarboxylic acid (TCA) cycle at the -ketoglutarate dehydrogenase (KGDH)/succinyl coenzyme-A synthetase step, metabolizing -ketoglutarate to succinate. Associated with this block we found aberrant protein S-nitrosylation of KGDH subunits that are known to inhibit enzyme function. This aberrant S-nitrosylation was documented not only in AD-hiN but also in postmortem human AD brains vs. controls, as assessed by two separate unbiased mass spectrometry platforms using both SNOTRAP identification of S-nitrosothiols and chemoselective-enrichment of S-nitrosoproteins. Treatment with dimethyl succinate a cell-permeable derivative of a TCA substrate downstream to the block resulted in partial rescue of mitochondrial bioenergetic function as well as improvement in synapse number in AD-hiN. Our findings have therapeutic implications as proof-of-principle that rescue of mitochondrial energy metabolism can ameliorate synaptic loss in hiPSC-based models of AD.

2024-05-24 | PXD042436 | Pride

RNA-seq of HUVECs stimulated with HG and oxLDL

Project description:We investigated the role of SNO-GNIA2 in HG+oxLDL-induced endothelial inflammation during the development of diabetes-accelerated atherosclerosis and found that SNO-GNAI2 could promote endothelial inflammation through dysregulating Hippo-YAP . We hypothesized that SNO-GNAI2 induced Hippo-YAP dysfunction through enhancing coupling and activating G-protein coupling receptors (GPCRs).

2021-06-02 | GSE173669 | GEO

Small nucleolar RNAs and small Cajal body-specific RNAs show distinct transcriptional profiles in the context of the molecular heterogeneity of multiple myeloma.

Project description:Small nucleolar RNAs (snoRNAs) and small Cajal body-specific RNAs (scaRNAs) are non-coding RNAs involved in the maturation of other RNA molecules and generally located in the introns of host genes. It is now emerging that altered sno/scaRNAs expression may play a pathological role in cancer. This study elucidates the patterns of sno/scaRNAs expression in multiple myeloma (MM), by profiling puri?ed malignant plasma cells from 55 MMs, 8 secondary plasma cell leukemias (sPCL) and 4 normal controls. Overall, a global sno/scaRNAs down-regulation was found in MMs and at more extent in sPCLs compared to normal plasma cells. Whereas SCARNA22 resulted the only sno/scaRNA characterizing the TC4 MM, TC2 group displayed a distinct sno/scaRNA signature overexpressing members of SNORD115 and SNORD116 families located in a region finely regulated by imprinting mechanism at 15q11. However, the imprinting center resulted overall hypomethylated in MMs independently of the SNORD115 and SNORD116 expression levels. Finally, integrative analyses with available gene expression and genome-wide data revealed the occurrence of significant sno/scaRNAs/host genes co-expression and the putative influence of allelic imbalances on specific snoRNAs expression. Our data extend the current view of sno/scaRNAs deregulation in cancer and add novel information into the bio-molecular complexity of plasma cell dyscrasias.

2013-06-25 | GSE39683 | GEO

Tribolium castaneum

Project description:Tribolium castaneum phosphine

| PRJNA297896 | ENA

Transcriptomic Characterization of Inhalation Phosphine Toxicity in Adult Male Sprague-Dawley Rats

Project description:Phosphine (PH3) is a highly toxic, corrosive, flammable, heavier-than-air gas that is a commonly used fumigant. Although the mechanism of toxicity is unclear, PH3 is thought to be a metabolic poison. PH3 exposure induces multi-organ toxicity and no effective antidotes or therapeutics have been identified. To better characterize the mechanism(s) driving PH3-induced toxicity we have performed transcriptomic analysis on conscious adult male Sprague-Dawley rats following whole-body inhalation exposure to phosphine gas at three concentrations. PH3 exposure induced concentration- and time-dependent changes in gene expression across multiple tissues.

2020-12-30 | GSE164007 | GEO

Transcriptomic Characterization of Inhalation Phosphine Toxicity in Adult Male Sprague-Dawley Rats (21,252 ppm x min)

2021-06-01 | GSE164019 | GEO