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Article ; Online: A ubiquitinome analysis to study the functional roles of the proteasome associated deubiquitinating enzymes USP14 and UCH37.

van der Wal, Lennart / Bezstarosti, Karel / Demmers, Jeroen A A

2022 Volume 262, Page(s) 104592

Abstract: The removal of (poly)ubiquitin chains at the proteasome is a key step in the protein degradation pathway that determines which proteins are degraded and ultimately decides cell fate. Three different deubiquitinating enzymes (DUBs) are associated to the ... ...

Abstract	The removal of (poly)ubiquitin chains at the proteasome is a key step in the protein degradation pathway that determines which proteins are degraded and ultimately decides cell fate. Three different deubiquitinating enzymes (DUBs) are associated to the human proteasome, PSMD14 (RPN11), USP14 and UCH37 (UCHL5). However, the functional roles and specificities of these proteasomal DUBs remain elusive. To reveal the specificities of proteasome associated DUBs, we used SILAC based quantitative ubiquitinomics to study the effects of CRISPR-Cas9 based knockout of each of these DUBs on the dynamic cellular ubiquitinome. We observed distinct effects on the global ubiquitinome upon removal of either USP14 or UCH37, while the simultaneous removal of both DUBs suggested less functional redundancy than previously anticipated. We also investigated whether the small molecule inhibitor b-AP15 has the potential to specifically target USP14 and UCH37 by comparing treatment of wild-type versus USP14/UCH37 double-knockout cells with this drug. Strikingly, broad and severe off-target effects were observed, questioning the alleged specificity of this inhibitor. In conclusion, this work presents novel insights into the function of proteasome associated DUBs and illustrates the power of in-depth ubiquitinomics for screening the activity of DUBs and of DUB modulating compounds. Significance: Introduction: The removal of (poly)ubiquitin chains at the proteasome is a key step in the protein degradation pathway that determines which proteins are degraded and ultimately decides cell fate. Three different deubiquitinating enzymes (DUBs) are associated to the human proteasome, PSMD14/RPN11, USP14 and UCH37/UCHL5. However, the functional roles and specificities of these proteasomal DUBs remains elusive. Materials & methods: We have applied a SILAC based quantitative ubiquitinomics to study the effects of CRISPR-Cas9 based knockout of each of these DUBs on the dynamic cellular ubiquitinome. Also, we have studied the function of the small molecule inhibitor b-AP15, which has the potential to specifically target USP14 and UCH37. Results: We report distinct effects on the ubiquitinome and the ability of the proteasome to clear proteins upon removal of either USP14 or UCH37, while the simultaneous removal of both DUBs suggests less redundancy than previously anticipated. In addition, broad and severe off-target effects were observed for b-AP15, questioning the alleged specificity of this inhibitor. Conclusions: This work presents novel insights into the function of proteasome associated DUBs and illustrates the power of in-depth ubiquitinomics for screening the activity of DUBs and of DUB modulating compounds.
MeSH term(s)	Humans ; Proteasome Endopeptidase Complex/metabolism ; Proteolysis ; Trans-Activators/metabolism ; Ubiquitin Thiolesterase/metabolism ; Ubiquitins/metabolism
Chemical Substances	PSMD14 protein, human ; Trans-Activators ; USP14 protein, human ; Ubiquitins ; UCHL5 protein, human (EC 3.4.19.12) ; Ubiquitin Thiolesterase (EC 3.4.19.12) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2022-04-27
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2400835-7
ISSN	1876-7737 ; 1874-3919
ISSN (online)	1876-7737
ISSN	1874-3919
DOI	10.1016/j.jprot.2022.104592
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Article ; Online: Detection of Protein Ubiquitination Sites by Peptide Enrichment and Mass Spectrometry.

Bezstarosti, Karel / van der Wal, Lennart / Demmers, Jeroen A A

Journal of visualized experiments : JoVE

2020 , Issue 157

Abstract: The posttranslational modification of proteins by the small protein ubiquitin is involved in many cellular events. After tryptic digestion of ubiquitinated proteins, peptides with a diglycine remnant conjugated to the epsilon amino group of lysine ('K-ε- ... ...

Abstract	The posttranslational modification of proteins by the small protein ubiquitin is involved in many cellular events. After tryptic digestion of ubiquitinated proteins, peptides with a diglycine remnant conjugated to the epsilon amino group of lysine ('K-ε-diglycine' or simply 'diGly') can be used to track back the original modification site. Efficient immunopurification of diGly peptides combined with sensitive detection by mass spectrometry has resulted in a huge increase in the number of ubiquitination sites identified up to date. We have made several improvements to this workflow, including offline high pH reverse-phase fractionation of peptides prior to the enrichment procedure, and the inclusion of more advanced peptide fragmentation settings in the ion routing multipole. Also, more efficient cleanup of the sample using a filter-based plug in order to retain the antibody beads results in a greater specificity for diGly peptides. These improvements result in the routine detection of more than 23,000 diGly peptides from human cervical cancer cells (HeLa) cell lysates upon proteasome inhibition in the cell. We show the efficacy of this strategy for in-depth analysis of the ubiquitinome profiles of several different cell types and of in vivo samples, such as brain tissue. This study presents an original addition to the toolbox for protein ubiquitination analysis to uncover the deep cellular ubiquitinome.
MeSH term(s)	Amino Acid Sequence ; Animals ; Bortezomib/pharmacology ; Cell Line, Tumor ; Humans ; Isotope Labeling ; Mass Spectrometry/methods ; Mice ; Peptides/chemistry ; Peptides/metabolism ; Ubiquitinated Proteins/analysis ; Ubiquitinated Proteins/chemistry ; Ubiquitination
Chemical Substances	Peptides ; Ubiquitinated Proteins ; Bortezomib (69G8BD63PP)
Language	English
Publishing date	2020-03-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Video-Audio Media
ZDB-ID	2259946-0
ISSN	1940-087X ; 1940-087X
ISSN (online)	1940-087X
ISSN	1940-087X
DOI	10.3791/59079
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Article ; Online: Microscopy-based single-cell proteomic profiling reveals heterogeneity in DNA damage response dynamics.

Su, Pin-Rui / You, Li / Beerens, Cecile / Bezstarosti, Karel / Demmers, Jeroen / Pabst, Martin / Kanaar, Roland / Hsu, Cheng-Chih / Chien, Miao-Ping

Cell reports methods

2022 Volume 2, Issue 6, Page(s) 100237

Abstract: Single-cell proteomics has the potential to decipher tumor heterogeneity, and a method like single-cell proteomics by mass spectrometry (SCoPE-MS) allows profiling several tens of single cells for >1,000 proteins per cell. This method, however, cannot ... ...

Abstract	Single-cell proteomics has the potential to decipher tumor heterogeneity, and a method like single-cell proteomics by mass spectrometry (SCoPE-MS) allows profiling several tens of single cells for >1,000 proteins per cell. This method, however, cannot link the proteome of individual cells with phenotypes of interest. Here, we developed a microscopy-based functional single-cell proteomic-profiling technology, called FUNpro, to address this. FUNpro enables screening, identification, and isolation of single cells of interest in a real-time fashion, even if the phenotypes are dynamic or the cells of interest are rare. We applied FUNpro to proteomically profile a newly identified small subpopulation of U2OS osteosarcoma cells displaying an abnormal, prolonged DNA damage response (DDR) after ionizing radiation (IR). With this, we identified the PDS5A protein contributing to the abnormal DDR dynamics and helping the cells survive after IR.
MeSH term(s)	DNA Damage ; Microscopy ; Proteomics/methods ; Cell Cycle Proteins ; Radiation, Ionizing
Chemical Substances	Cell Cycle Proteins
Language	English
Publishing date	2022-06-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2667-2375
ISSN (online)	2667-2375
DOI	10.1016/j.crmeth.2022.100237
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Article: A ubiquitinome analysis to study the functional roles of the proteasome associated deubiquitinating enzymes USP14 and UCH37

van der Wal, Lennart / Bezstarosti, Karel / Demmers, Jeroen A.A.

Journal of proteomics. 2022 June 30, v. 262

2022

Abstract	The removal of (poly)ubiquitin chains at the proteasome is a key step in the protein degradation pathway that determines which proteins are degraded and ultimately decides cell fate. Three different deubiquitinating enzymes (DUBs) are associated to the human proteasome, PSMD14 (RPN11), USP14 and UCH37 (UCHL5). However, the functional roles and specificities of these proteasomal DUBs remain elusive. To reveal the specificities of proteasome associated DUBs, we used SILAC based quantitative ubiquitinomics to study the effects of CRISPR-Cas9 based knockout of each of these DUBs on the dynamic cellular ubiquitinome. We observed distinct effects on the global ubiquitinome upon removal of either USP14 or UCH37, while the simultaneous removal of both DUBs suggested less functional redundancy than previously anticipated. We also investigated whether the small molecule inhibitor b-AP15 has the potential to specifically target USP14 and UCH37 by comparing treatment of wild-type versus USP14/UCH37 double-knockout cells with this drug. Strikingly, broad and severe off-target effects were observed, questioning the alleged specificity of this inhibitor. In conclusion, this work presents novel insights into the function of proteasome associated DUBs and illustrates the power of in-depth ubiquitinomics for screening the activity of DUBs and of DUB modulating compounds. Introduction: The removal of (poly)ubiquitin chains at the proteasome is a key step in the protein degradation pathway that determines which proteins are degraded and ultimately decides cell fate. Three different deubiquitinating enzymes (DUBs) are associated to the human proteasome, PSMD14/RPN11, USP14 and UCH37/UCHL5. However, the functional roles and specificities of these proteasomal DUBs remains elusive. Materials & Methods: We have applied a SILAC based quantitative ubiquitinomics to study the effects of CRISPR-Cas9 based knockout of each of these DUBs on the dynamic cellular ubiquitinome. Also, we have studied the function of the small molecule inhibitor b-AP15, which has the potential to specifically target USP14 and UCH37. Results: We report distinct effects on the ubiquitinome and the ability of the proteasome to clear proteins upon removal of either USP14 or UCH37, while the simultaneous removal of both DUBs suggests less redundancy than previously anticipated. In addition, broad and severe off-target effects were observed for b-AP15, questioning the alleged specificity of this inhibitor. Conclusions: This work presents novel insights into the function of proteasome associated DUBs and illustrates the power of in-depth ubiquitinomics for screening the activity of DUBs and of DUB modulating compounds.
Keywords	CRISPR-Cas systems ; drugs ; humans ; proteasome endopeptidase complex ; protein degradation ; proteomics ; ubiquitin
Language	English
Dates of publication	2022-0630
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	2400835-7
ISSN	1876-7737 ; 1874-3919
ISSN (online)	1876-7737
ISSN	1874-3919
DOI	10.1016/j.jprot.2022.104592
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Article ; Online: Ubiquitinome Profiling Reveals in Vivo UBE2D3 Targets and Implicates UBE2D3 in Protein Quality Control.

Yalçin, Zeliha / Koot, Daniëlle / Bezstarosti, Karel / Salas-Lloret, Daniel / Bleijerveld, Onno B / Boersma, Vera / Falcone, Mattia / González-Prieto, Román / Altelaar, Maarten / Demmers, Jeroen A A / Jacobs, Jacqueline J L

Molecular & cellular proteomics : MCP

2023 Volume 22, Issue 6, Page(s) 100548

Abstract: Ubiquitination has crucial roles in many cellular processes, and dysregulation of ubiquitin machinery enzymes can result in various forms of pathogenesis. Cells only have a limited set of ubiquitin-conjugating (E2) enzymes to support the ubiquitination ... ...

Abstract	Ubiquitination has crucial roles in many cellular processes, and dysregulation of ubiquitin machinery enzymes can result in various forms of pathogenesis. Cells only have a limited set of ubiquitin-conjugating (E2) enzymes to support the ubiquitination of many cellular targets. As individual E2 enzymes have many different substrates and interactions between E2 enzymes and their substrates can be transient, it is challenging to define all in vivo substrates of an individual E2 and the cellular processes it affects. Particularly challenging in this respect is UBE2D3, an E2 enzyme with promiscuous activity in vitro but less defined roles in vivo. Here, we set out to identify in vivo targets of UBE2D3 by using stable isotope labeling by amino acids in cell culture-based and label-free quantitative ubiquitin diGly proteomics to study global proteome and ubiquitinome changes associated with UBE2D3 depletion. UBE2D3 depletion changed the global proteome, with the levels of proteins from metabolic pathways, in particular retinol metabolism, being the most affected. However, the impact of UBE2D3 depletion on the ubiquitinome was much more prominent. Interestingly, molecular pathways related to mRNA translation were the most affected. Indeed, we find that ubiquitination of the ribosomal proteins RPS10 and RPS20, critical for ribosome-associated protein quality control, is dependent on UBE2D3. We show by Targets of Ubiquitin Ligases Identified by Proteomics 2 methodology that RPS10 and RPS20 are direct targets of UBE2D3 and demonstrate that the catalytic activity of UBE2D3 is required to ubiquitinate RPS10 in vivo. In addition, our data suggest that UBE2D3 acts at multiple levels in autophagic protein quality control. Collectively, our findings show that depletion of an E2 enzyme in combination with quantitative diGly-based ubiquitinome profiling is a powerful tool to identify new in vivo E2 substrates, as we have done here for UBE2D3. Our work provides an important resource for further studies on the in vivo functions of UBE2D3.
MeSH term(s)	Proteome/metabolism ; Ubiquitination ; Ubiquitin/metabolism ; Ubiquitin-Conjugating Enzymes/genetics ; Ubiquitin-Conjugating Enzymes/metabolism ; Ubiquitin-Protein Ligases/metabolism
Chemical Substances	Proteome ; Ubiquitin ; Ubiquitin-Conjugating Enzymes (EC 2.3.2.23) ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
Language	English
Publishing date	2023-04-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	2075924-1
ISSN	1535-9484 ; 1535-9476
ISSN (online)	1535-9484
ISSN	1535-9476
DOI	10.1016/j.mcpro.2023.100548
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Article: Detection of protein ubiquitination sites by peptide enrichment and mass spectrometry

Bezstarosti, Karel / van der Wal, Lennart / Demmers, Jeroen A. A

Journal of visualized experiments. 2020 Mar. 23, , no. 157

2020

Abstract	The posttranslational modification of proteins by the small protein ubiquitin is involved in many cellular events. After tryptic digestion of ubiquitinated proteins, peptides with a diglycine remnant conjugated to the epsilon amino group of lysine ('K-ε-diglycine' or simply 'diGly') can be used to track back the original modification site. Efficient immunopurification of diGly peptides combined with sensitive detection by mass spectrometry has resulted in a huge increase in the number of ubiquitination sites identified up to date. We have made several improvements to this workflow, including offline high pH reverse-phase fractionation of peptides prior to the enrichment procedure, and the inclusion of more advanced peptide fragmentation settings in the ion routing multipole. Also, more efficient cleanup of the sample using a filter-based plug in order to retain the antibody beads results in a greater specificity for diGly peptides. These improvements result in the routine detection of more than 23,000 diGly peptides from human cervical cancer cells (HeLa) cell lysates upon proteasome inhibition in the cell. We show the efficacy of this strategy for in-depth analysis of the ubiquitinome profiles of several different cell types and of in vivo samples, such as brain tissue. This study presents an original addition to the toolbox for protein ubiquitination analysis to uncover the deep cellular ubiquitinome.
Keywords	antibodies ; brain ; enzymatic hydrolysis ; enzyme inhibition ; fractionation ; human diseases ; lysine ; mass spectrometry ; neoplasm cells ; pH ; peptides ; proteasome endopeptidase complex ; ubiquitin ; ubiquitination ; uterine cervical neoplasms
Language	English
Dates of publication	2020-0323
Size	p. e59079.
Publishing place	Journal of Visualized Experiments
Document type	Article
ZDB-ID	2259946-0
ISSN	1940-087X
ISSN	1940-087X
DOI	10.3791/59079
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Targeted Proteomics for the Detection of SARS-CoV-2 Proteins

Bezstarosti, Karel / Lamers, Mart M. / Haagmans, Bart L. / Demmers, Jeroen A. A.

bioRxiv

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). The rapid, sensitive and specific diagnosis of SARS-CoV-2 by fast and unambiguous testing is widely recognized to be critical in ... ...

Abstract	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). The rapid, sensitive and specific diagnosis of SARS-CoV-2 by fast and unambiguous testing is widely recognized to be critical in responding the current outbreak. Since the current testing capacity by conventional PCR based methods is insufficient because of shortages of supplies such as RNA extraction kits and PCR reagents, alternative and/or complementary testing assays should be developed. Here, we exploit the potential of targeted mass spectrometry based proteomic technologies to solve the current issue of insufficient SARS-CoV-2 diagnostic testing capacity. We have assessed the limit of detection by parallel reaction monitoring (PRM) on an Orbitrap Eclipse mass spectrometer for target tryptic peptides of several SARS-CoV-2 proteins from a sample of virus infected Vero cells. For Nucleocapsid protein the limit of detection was found to be in the mid-attomole range (0.9 × 10−12 g), which would theoretically correspond to approximately 10,000 SARS-CoV-2 particles, under the assumption that all viral proteins are assembled in macromolecular virus particles. Whether or not this sensitivity is sufficient to play a role in SARS-CoV-2 detection in patient material such as swabs or body fluids largely depends on the amount of viral proteins present in such samples and is subject of further research. If yes, mass spectrometry based methods could serve as a complementary protein based diagnostic tool and further steps should be focused on sample preparation protocols and on improvements in sample throughput.
Keywords	covid19
Publisher	BioRxiv; WHO
Document type	Article ; Online
DOI	10.1101/2020.04.23.057810
Database	COVID19

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Article ; Online: Matrix Metalloproteinase-7 in Urinary Extracellular Vesicles Identifies Rapid Disease Progression in Autosomal Dominant Polycystic Kidney Disease.

van Heugten, Martijn H / Blijdorp, Charles J / Arjune, Sita / van Willigenburg, Hester / Bezstarosti, Karel / Demmers, Jeroen A A / Musterd-Bhaggoe, Usha / Meijer, Esther / Gansevoort, Ron T / Zietse, Robert / Hayat, Sikander / Kramann, Rafael / Müller, Roman-Ulrich / Salih, Mahdi / Hoorn, Ewout J

Journal of the American Society of Nephrology : JASN

2023 Volume 35, Issue 3, Page(s) 321–334

Abstract: Significance statement: There is an unmet need for biomarkers of disease progression in autosomal dominant polycystic kidney disease (ADPKD). This study investigated urinary extracellular vesicles (uEVs) as a source of such biomarkers. Proteomic ... ...

Abstract	Significance statement: There is an unmet need for biomarkers of disease progression in autosomal dominant polycystic kidney disease (ADPKD). This study investigated urinary extracellular vesicles (uEVs) as a source of such biomarkers. Proteomic analysis of uEVs identified matrix metalloproteinase 7 (MMP-7) as a biomarker predictive of rapid disease progression. In validation studies, MMP-7 was predictive in uEVs but not in whole urine, possibly because uEVs are primarily secreted by tubular epithelial cells. Indeed, single-nucleus RNA sequencing showed that MMP-7 was especially increased in proximal tubule and thick ascending limb cells, which were further characterized by a profibrotic phenotype. Together, these data suggest that MMP-7 is a biologically plausible and promising uEV biomarker for rapid disease progression in ADPKD. Background: In ADPKD, there is an unmet need for early markers of rapid disease progression to facilitate counseling and selection for kidney-protective therapy. Our aim was to identify markers for rapid disease progression in uEVs. Methods: Six paired case-control groups ( n =10-59/group) of cases with rapid disease progression and controls with stable disease were formed from two independent ADPKD cohorts, with matching by age, sex, total kidney volume, and genetic variant. Candidate uEV biomarkers were identified by mass spectrometry and further analyzed using immunoblotting and an ELISA. Single-nucleus RNA sequencing of healthy and ADPKD tissue was used to identify the cellular origin of the uEV biomarker. Results: In the discovery proteomics experiments, the protein abundance of MMP-7 was significantly higher in uEVs of patients with rapid disease progression compared with stable disease. In the validation groups, a significant >2-fold increase in uEV-MMP-7 in patients with rapid disease progression was confirmed using immunoblotting. By contrast, no significant difference in MMP-7 was found in whole urine using ELISA. Compared with healthy kidney tissue, ADPKD tissue had significantly higher MMP-7 expression in proximal tubule and thick ascending limb cells with a profibrotic phenotype. Conclusions: Among patients with ADPKD, rapid disease progressors have higher uEV-associated MMP-7. Our findings also suggest that MMP-7 is a biologically plausible biomarker for more rapid disease progression.
MeSH term(s)	Humans ; Biomarkers ; Disease Progression ; Extracellular Vesicles ; Matrix Metalloproteinase 7 ; Polycystic Kidney, Autosomal Dominant/genetics ; Proteomics
Chemical Substances	Biomarkers ; Matrix Metalloproteinase 7 (EC 3.4.24.23) ; MMP7 protein, human (EC 3.4.24.23)
Language	English
Publishing date	2023-12-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	1085942-1
ISSN	1533-3450 ; 1046-6673
ISSN (online)	1533-3450
ISSN	1046-6673
DOI	10.1681/ASN.0000000000000277
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Article ; Online: Distinct proteomic profiles in prefrontal subareas of elderly major depressive disorder and bipolar disorder patients.

Qi, Yang-Jian / Lu, Yun-Rong / Shi, Li-Gen / Demmers, Jeroen A A / Bezstarosti, Karel / Rijkers, Erikjan / Balesar, Rawien / Swaab, Dick / Bao, Ai-Min

Translational psychiatry

2022 Volume 12, Issue 1, Page(s) 275

Abstract: We investigated for the first time the proteomic profiles both in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) of major depressive disorder (MDD) and bipolar disorder (BD) patients. Cryostat sections of DLPFC and ACC of ... ...

Abstract	We investigated for the first time the proteomic profiles both in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) of major depressive disorder (MDD) and bipolar disorder (BD) patients. Cryostat sections of DLPFC and ACC of MDD and BD patients with their respective well-matched controls were used for study. Proteins were quantified by tandem mass tag and high-performance liquid chromatography-mass spectrometry system. Gene Ontology terms and functional cluster alteration were analyzed through bioinformatic analysis. Over 3000 proteins were accurately quantified, with more than 100 protein expressions identified as significantly changed in these two brain areas of MDD and BD patients as compared to their respective controls. These include OGDH, SDHA and COX5B in the DLPFC in MDD patients; PFN1, HSP90AA1 and PDCD6IP in the ACC of MDD patients; DBN1, DBNL and MYH9 in the DLPFC in BD patients. Impressively, depending on brain area and distinct diseases, the most notable change we found in the DLPFC of MDD was 'suppressed energy metabolism'; in the ACC of MDD it was 'suppressed tissue remodeling and suppressed immune response'; and in the DLPFC of BD it was differentiated 'suppressed tissue remodeling and suppressed neuronal projection'. In summary, there are distinct proteomic changes in different brain areas of the same mood disorder, and in the same brain area between MDD and BD patients, which strengthens the distinct pathogeneses and thus treatment targets.
MeSH term(s)	Aged ; Bipolar Disorder ; Depressive Disorder, Major ; Gyrus Cinguli ; Humans ; Magnetic Resonance Imaging/methods ; Profilins/metabolism ; Proteomics
Chemical Substances	PFN1 protein, human ; Profilins
Language	English
Publishing date	2022-07-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2609311-X
ISSN	2158-3188 ; 2158-3188
ISSN (online)	2158-3188
ISSN	2158-3188
DOI	10.1038/s41398-022-02040-7
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Article: DDA1, a novel factor in transcription-coupled repair, modulates CRL4

Research square

2023

Abstract: Transcription-blocking DNA lesions are specifically targeted by transcription-coupled nucleotide excision repair (TC-NER), which removes a broad spectrum of DNA lesions to preserve transcriptional output and thereby cellular homeostasis to counteract ... ...

Abstract	Transcription-blocking DNA lesions are specifically targeted by transcription-coupled nucleotide excision repair (TC-NER), which removes a broad spectrum of DNA lesions to preserve transcriptional output and thereby cellular homeostasis to counteract aging. TC-NER is initiated by the stalling of RNA polymerase II at DNA lesions, which triggers the assembly of the TC-NER-specific proteins CSA, CSB and UVSSA. CSA, a WD40-repeat containing protein, is the substrate receptor subunit of a cullin-RING ubiquitin ligase complex composed of DDB1, CUL4A/B and RBX1 (CRL4
Language	English
Publishing date	2023-10-12
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3385435/v1
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