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Musunuri, Sravani
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Publications (10 of 14) Show all publications
Almandoz-Gil, L., Welander, H., Ihse, E., Khoonsari, P. E., Musunuri, S., Lendel, C., . . . Bergström, J. (2018). Corrigendum to “Low molar excess of 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote oligomerization of alpha-synuclein through different pathways” [Free Rad. Biol. Med. (2017) 421–431]. Free Radical Biology & Medicine, 117, 258-258
Open this publication in new window or tab >>Corrigendum to “Low molar excess of 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote oligomerization of alpha-synuclein through different pathways” [Free Rad. Biol. Med. (2017) 421–431]
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2018 (English)In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 117, p. 258-258Article in journal (Refereed) Published
National Category
Biochemistry and Molecular Biology Engineering and Technology
Identifiers
urn:nbn:se:uu:diva-356238 (URN)10.1016/j.freeradbiomed.2018.02.007 (DOI)000427420600025 ()29455934 (PubMedID)
Note

Correction to: Free Radical Biology & Medicine, vol. 110, pages 421-431.

DOI: 10.1016/j.freeradbiomed.2017.07.004

WoS title: Low molar excess of 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote oligomerization of alpha-synuclein through different pathways (vol 110, pg 421, 2017)

Available from: 2018-07-27 Created: 2018-07-27 Last updated: 2019-04-29Bibliographically approved
Karademir, B., Sari, G., Jannuzzi, A. T., Musunuri, S., Wicher, G., Grune, T., . . . Jung, T. (2018). Proteomic approach for understanding milder neurotoxicity of Carfilzomib against Bortezomib. Scientific Reports, 8, Article ID 16318.
Open this publication in new window or tab >>Proteomic approach for understanding milder neurotoxicity of Carfilzomib against Bortezomib
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 16318Article in journal (Refereed) Published
Abstract [en]

The proteasomal system is responsible for the turnover of damaged proteins. Because of its important functions in oncogenesis, inhibiting the proteasomal system is a promising therapeutic approach for cancer treatment. Bortezomib (BTZ) is the first proteasome inhibitor approved by FDA for clinical applications. However neuropathic side effects are dose limiting for BTZ as many other chemotherapeutic agents. Therefore second-generation proteasome inhibitors have been developed including carfilzomib (CFZ). Aim of the present work was investigating the mechanisms of peripheral neuropathy triggered by the proteasome inhibitor BTZ and comparing the pathways affected by BTZ and CFZ, respectively. Neural stem cells, isolated from the cortex of E14 mouse embryos, were treated with BTZ and CFZ and mass spectrometry was used to compare the global protein pool of treated cells. BTZ was shown to cause more severe cytoskeletal damage, which is crucial in neural cell integrity. Excessive protein carbonylation and actin filament destabilization were also detected following BTZ treatment that was lower following CFZ treatment. Our data on cytoskeletal proteins, chaperone system, and protein oxidation may explain the milder neurotoxic effects of CFZ in clinical applications.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-369397 (URN)10.1038/s41598-018-34507-3 (DOI)000449272100012 ()30397214 (PubMedID)
Funder
Swedish Research Council, 2015-4870
Available from: 2018-12-12 Created: 2018-12-12 Last updated: 2018-12-12Bibliographically approved
Abu Hamdeh, S., Shevchenko, G., Mi, J., Musunuri, S., Bergquist, J. & Marklund, N. (2018). Proteomic differences between focal and diffuse traumatic brain injury in human brain tissue. Scientific Reports, 8, Article ID 6807.
Open this publication in new window or tab >>Proteomic differences between focal and diffuse traumatic brain injury in human brain tissue
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 6807Article in journal (Refereed) Published
Abstract [en]

The early molecular response to severe traumatic brain injury (TBI) was evaluated using biopsies of structurally normal-appearing cortex, obtained at location for intracranial pressure (ICP) monitoring, from 16 severe TBI patients. Mass spectrometry (MS; label free and stable isotope dimethyl labeling) quantitation proteomics showed a strikingly different molecular pattern in TBI in comparison to cortical biopsies from 11 idiopathic normal pressure hydrocephalus patients. Diffuse TBI showed increased expression of peptides related to neurodegeneration (Tau and Fascin, p < 0.05), reduced expression related to antioxidant defense (Glutathione S-transferase Mu 3, Peroxiredoxin-6, Thioredoxin-dependent peroxide reductase; p < 0.05) and increased expression of potential biomarkers (e.g. Neurogranin, Fatty acid-binding protein, heart p < 0.05) compared to focal TBI. Proteomics of human brain biopsies displayed considerable molecular heterogeneity among the different TBI subtypes with consequences for the pathophysiology and development of targeted treatments for TBI.

National Category
Neurosciences Neurology
Identifiers
urn:nbn:se:uu:diva-341912 (URN)10.1038/s41598-018-25060-0 (DOI)000431113100005 ()29717219 (PubMedID)
Funder
The Swedish Brain FoundationVINNOVASwedish Research CouncilLars Hierta Memorial FoundationStiftelsen Gamla Tjänarinnor
Available from: 2018-02-15 Created: 2018-02-15 Last updated: 2018-07-13Bibliographically approved
Abu Hamdeh, S., Shevchenko, G., Mi, J., Musunuri, S., Bergquist, J. & Marklund, N. (2018). Proteomic Differences Between Focal And Diffuse Traumatic Brain Injury In Human Brain Tissue. Paper presented at 3rd Joint Symposium of the International-and-National-Neurotrauma-Societies-and-AANS/CNS-Section on Neurotrauma and Critical Care, AUG 11-16, 2018, Toronto, CANADA. Journal of Neurotrauma, 35(16), A238-A239
Open this publication in new window or tab >>Proteomic Differences Between Focal And Diffuse Traumatic Brain Injury In Human Brain Tissue
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2018 (English)In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 35, no 16, p. A238-A239Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
MARY ANN LIEBERT, INC, 2018
Keywords
Biomarker, White Matter
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:uu:diva-363873 (URN)000441527400640 ()
Conference
3rd Joint Symposium of the International-and-National-Neurotrauma-Societies-and-AANS/CNS-Section on Neurotrauma and Critical Care, AUG 11-16, 2018, Toronto, CANADA
Available from: 2018-11-14 Created: 2018-11-14 Last updated: 2018-11-14Bibliographically approved
Almandoz-Gil, L., Welander, H., Ihse, E., Khoonsari, P. E., Musunuri, S., Lendel, C., . . . Bergström, J. (2017). Low molar excess of 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote oligomerization of alpha-synuclein through different pathways. Free Radical Biology & Medicine, 110, 421-431
Open this publication in new window or tab >>Low molar excess of 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote oligomerization of alpha-synuclein through different pathways
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2017 (English)In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 110, p. 421-431Article in journal (Refereed) Published
Abstract [en]

Aggregated alpha-synuclein is the main component of Lewy bodies, intraneuronal inclusions found in brains with Parkinson's disease and dementia with Lewy bodies. A body of evidence implicates oxidative stress in the pathogenesis of these diseases. For example, a large excess (30:1, aldehyde:protein) of the lipid peroxidation end products 4-oxo-2-nonenal (ONE) or 4-hydroxy-2-nonenal (HNE) can induce alpha-synuclein oligomer formation. The objective of the study was to investigate the effect of these reactive aldehydes on alpha-synuclein at a lower molar excess (3:1) at both physiological (7.4) and acidic (5.4) pH. As observed by size-exclusion chromatography, ONE rapidly induced the formation of alpha-synuclein oligomers at both pH values, but the effect was less pronounced under the acidic condition. In contrast, only a small proportion of alpha-synuclein oligomers were formed with low excess HNE-treatment at physiological pH and no oligomers at all under the acidic condition. With prolonged incubation times (up to 96 h), more alpha-synuclein was oligomerized at physiological pH for both ONE and HNE. As determined by Western blot, ONE-oligomers were more SDS-stable and to a higher-degree cross-linked as compared to the HNE-induced oligomers. However, as shown by their greater sensitivity to proteinase K treatment, ONE-oligomers, exhibited a less compact structure than HNE-oligomers. As indicated by mass spectrometry, ONE modified most Lys residues, whereas HNE primarily modified the His50 residue and fewer Lys residues, albeit to a higher degree than ONE. Taken together, our data show that the aldehydes ONE and HNE can modify alpha-synuclein and induce oligomerization, even at low molar excess, but to a higher degree at physiological pH and seemingly through different pathways.

Keywords
Alpha-synuclein, Oligomers, 4-oxo-2-nonenal, 4-hydroxy-2-nonenal, Oxidative stress
National Category
Medical and Health Sciences Engineering and Technology Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-326663 (URN)10.1016/j.freeradbiomed.2017.07.004 (DOI)000406049200038 ()28690195 (PubMedID)
Funder
Swedish Research Council, 2011-4519, 2012-2172, 2010-6745Marianne and Marcus Wallenberg FoundationThe Swedish Brain FoundationSwedish Society of MedicineÅke Wiberg Foundation
Note

Correction in: Free Radical Biology and Medicine, vol. 117, pages 258-258.

DOI: 10.1016/j.freeradbiomed.2018.02.007

Available from: 2017-07-19 Created: 2017-07-19 Last updated: 2019-04-29Bibliographically approved
Warnecke, A., Musunuri, S., N'diaye, M., Sandalova, T., Achour, A., Bergquist, J. & Harris, R. A. (2017). Nitration of MOG diminishes its encephalitogenicity depending on MHC haplotype. Journal of Neuroimmunology, 303, 1-12
Open this publication in new window or tab >>Nitration of MOG diminishes its encephalitogenicity depending on MHC haplotype
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2017 (English)In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 303, p. 1-12Article in journal (Refereed) Published
Abstract [en]

Post-translational modifications of autoantigens are hypothesized to affect their immunogenicity. We here report that nitration of tyrosine 40 in Myelin Oligodendrocyte Glycoprotein (MOG) abrogates its encephalitogenicity both at protein and peptide levels in the experimental autoimmune encephalomyelitis (EAE) model in H2(b) C57BL/6 mice. Furthermore, nitrated MOG displays inferior antigen-specific proliferation of 2D2 splenocytes in vitro. Conversely, H2(q) DBA1 mice remain fully susceptible to EAE induction using nitrated MOG as the dominant epitope of H2q mice is unaltered. Molecular modeling analysis of the MOG(35-55)/H2-lA(b) complex and bioinformatics peptide binding predictions indicate that the lack of T cell reactivity towards nitrated MOG can be attributed to the inability of murine H2-IA(b) to efficiently present the altered peptide ligand of MOG(35-55) because the nitrated tyrosine 40 cannot be accommodated in the p1 anchor pocket. In conclusion we demonstrate nitration as a relevant determinant affecting T cell recognition of carrier antigen depending on MHC haplotype. Our data have implications for understanding the role of post-translationally modified antigen in autoimmunity. (C) 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license.

Keywords
3-Nitrotyrosine, Post-translational modification, Myelin oligodendrocyte glycoprotein, Experimental autoimmune encephalomyelitis, Antigen presentation, Major histocompatibility complex, Autoimmunity, Oxidative stress, Epitope spreading
National Category
Neurosciences Immunology
Identifiers
urn:nbn:se:uu:diva-317945 (URN)10.1016/j.jneuroim.2016.11.008 (DOI)000393629100001 ()28011088 (PubMedID)
Available from: 2017-04-01 Created: 2017-04-01 Last updated: 2018-01-13Bibliographically approved
Warnecke, A., Abele, S., Musunuri, S., Bergquist, J. & Harris, R. A. (2017). Scavenger Receptor A Mediates the Clearance and Immunological Screening of MDA-Modified Antigen by M2-Type Macrophages. Neuromolecular medicine, 19(4), 463-479
Open this publication in new window or tab >>Scavenger Receptor A Mediates the Clearance and Immunological Screening of MDA-Modified Antigen by M2-Type Macrophages
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2017 (English)In: Neuromolecular medicine, ISSN 1535-1084, E-ISSN 1559-1174, Vol. 19, no 4, p. 463-479Article in journal (Refereed) Published
Abstract [en]

In this study, we investigated the uptake of malondialdehyde (MDA)-modified myelin oligodendrocyte glycoprotein (MOG) in the context of lipid peroxidation and its implications in CNS autoimmunity. The use of custom-produced fluorescently labeled versions of MOG or MDA-modified MOG enabled us to study and quantify the uptake by different macrophage populations and to identify the responsible receptor, namely SRA. The SRA-mediated uptake of MDA-modified MOG is roughly tenfold more efficient compared to that of the native form. Notably, this uptake is most strongly associated with anti-inflammatory M2-type macrophages. MDA-modified MOG was demonstrated to be resistant to degradation by lysine-dependent proteases in vitro, but the overall digestion fragments appeared to be similar in cell lysates, although their relative abundance appeared to be altered as a result of faster uptake. Accordingly, MDA-modified MOG is processed for presentation by APCs, allowing maximized recall proliferation of MOG(35-55)-specific 2D2 T cells in vitro due to higher uptake. However, MDA modification of MOG did not enhance immune priming or disease course in the in vivo MOG-EAE model, but did induce antibody responses to both MOG and MDA adducts. Taken together our results indicate that MDA adducts primarily constitute clearance signals for phagocytes and promote rapid removal of antigen, which is subjected to immunological screening by previously licensed T cells.

Keywords
Malondialdeyde, Macrophages, MOG-EAE, Autoimmunity, Scavenger receptors, Posttranslational modifications
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-342212 (URN)10.1007/s12017-017-8461-y (DOI)000415009400001 ()28828577 (PubMedID)
Available from: 2018-02-20 Created: 2018-02-20 Last updated: 2018-02-20Bibliographically approved
Sravani, M., Emami Khoonsari, P., Mikus, M., Wetterhall, M., Häggmark, A., Lannfelt, L., . . . Kultima, K. (2016). Increased levels of extracellular microvesicle markers and decreased levels of endocytic/exocytic proteins in the Alzheimer’s disease brain. Journal of Alzheimer's Disease, 54(4), 1671-1686
Open this publication in new window or tab >>Increased levels of extracellular microvesicle markers and decreased levels of endocytic/exocytic proteins in the Alzheimer’s disease brain
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2016 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 54, no 4, p. 71p. 1671-1686Article in journal (Refereed) Published
Abstract [en]

Background: Alzheimer's disease (AD) is a chronic neurodegenerative disorder accounting for more than 50% of all dementia cases. AD neuropathology is characterized by the formation of extracellular plaques and intracellular neurofibrillary tangles consisting of aggregated amyloid-beta and tau, respectively. The disease mechanism has only been partially elucidated and is believed to also involve many other proteins.

Objective: This study intended to perform a proteomic profiling of post mortem AD brains and compare it with control brains as well as brains from other neurological diseases to gain insight into the disease pathology.

Methods: Here we used label-free shotgun mass spectrometry to analyze temporal neocortex samples from AD, other neurological disorders, and non-demented controls, in order to identify additional proteins that are altered in AD. The mass spectrometry results were verified by antibody suspension bead arrays.

Results: We found 50 proteins with altered levels between AD and control brains. The majority of these proteins were found at lower levels in AD. Pathway analyses revealed that several of the decreased proteins play a role in exocytic and endocytic pathways, whereas several of the increased proteins are related to extracellular vesicles. Using antibody-based analysis, we verified the mass spectrometry results for five representative proteins from this group of proteins (CD9, HSP72, PI42A, TALDO, and VAMP2) and GFAP, a marker for neuroinflammation.

Conclusions: Several proteins involved in exo-endocytic pathways and extracellular vesicle functions display altered levels in the AD brain. We hypothesize that such changes may result in disturbed cellular clearance and a perturbed cell-to-cell communication that may contribute to neuronal dysfunction and cell death in AD.

Publisher
p. 71
Keywords
Brain, Proteomics, Mass spectrometry, Alzheimer's disease
National Category
Analytical Chemistry Geriatrics Neurosciences
Research subject
Chemistry with specialization in Analytical Chemistry
Identifiers
urn:nbn:se:uu:diva-277617 (URN)10.3233/JAD-160271 (DOI)000386749900034 ()27636840 (PubMedID)
Funder
VINNOVALars Hierta Memorial FoundationSwedish Research Council, P29797-1; 621-2011-4423Knut and Alice Wallenberg FoundationStiftelsen Gamla Tjänarinnor
Available from: 2016-02-22 Created: 2016-02-22 Last updated: 2019-04-29Bibliographically approved
Musunuri, S. (2016). Mass Spectrometry-based Neuroproteomics: Deciphering the Human Brain Proteome. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Mass Spectrometry-based Neuroproteomics: Deciphering the Human Brain Proteome
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mammalian brain is challenging to study due to its heterogeneity and complexity. However, recent advances in molecular imaging, genomics and proteomics have contributed significantly to achieve insights into molecular basis of brain function and pathogenesis of neurological disorders. Efficient sample preparation is an integral part of a successful mass spectrometry (MS)-based proteomics. Apart from the identification, quantification of proteins is needed to investigate the alterations between proteome profiles from different sample sets. Therefore, this thesis investigates optimizing and application of the MS compatible sample preparation techniques for the identification and quantification of proteins from brain tissue.

The central objective of this thesis was (i) to improve the extraction of proteins as well as membrane proteins (MPs) from the brain tissue and (ii) to apply the optimized method along with the stable isotope dimethyl labeling (DML) and label-free (LF) MS approaches for the relative quantification of the brain proteome profiles during neurological conditions such as Alzheimer’s disease (AD) and traumatic brain injury (TBI).  First study described in this thesis is focused on the qualitative aspects for the brain tissue sample preparation. The optimized extraction buffers from first study containing n-octyl-β-glucopyranside or triton X-114 were used in the further quantitative studies to extract the proteins from patient (AD or TBI) and control human brain samples. Triton X-114 has additional advantage of separating MPs into a micellar phase. Therefore we also investigated the possibility to apply this in combination with DML quantitation approach for enrichment of low abundant MPs from AD brains.

AD and TBI causes severe socio-economic burden on the society and therefore there is a need to develop diagnostic markers to detect the early changes in the pathology of the disease. Analytical tools and techniques applied and discussed in this thesis for neuroproteomics applications proved to be powerful and reliable for analyzing complex biological samples to generate high-throughput screening and unbiased identification and quantitation of disease-specific proteins that are of great importance in understanding the disease pathology. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. p. 70
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1347
Keywords
Brain, Proteomics, Mass spectrometry, Alzheimer's disease, Traumatic brain injury, Membrane proteins, Sample preparation
National Category
Analytical Chemistry
Research subject
Chemistry with specialization in Analytical Chemistry
Identifiers
urn:nbn:se:uu:diva-277613 (URN)978-91-554-9485-8 (ISBN)
Public defence
2016-04-08, B42, BMC, Husargatan 3, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2016-03-18 Created: 2016-02-22 Last updated: 2016-04-04
Musunuri, S., Kultima, K., Richard, B. C., Ingelsson, M., Lannfelt, L., Bergquist, J. & Shevchenko, G. (2015). Micellar extraction possesses a new advantage for the analysis of Alzheimer's disease brain proteome. Analytical and Bioanalytical Chemistry, 407(4), 1041-1057
Open this publication in new window or tab >>Micellar extraction possesses a new advantage for the analysis of Alzheimer's disease brain proteome
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2015 (English)In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 407, no 4, p. 1041-1057Article in journal (Refereed) Published
Abstract [en]

Integral membrane proteins (MPs), such as transporters, receptors, and ion channels, are of great interest because of their participation in various vital cellular functions including cell-cell interactions, ion transport, and signal transduction. However, studies of MPs are complicated because of their hydrophobic nature, heterogeneity, and low abundance. Cloud-point extraction (CPE) with the non-ionic surfactant Triton X-114 was performed to simultaneously extract and phase separate hydrophobic and hydrophilic proteins from Alzheimer's disease (AD) and unaffected control brain tissue. Quantitative proteomics analysis of temporal neocortex samples of AD patients and controls was performed using a shotgun approach based on stable isotope dimethyl labeling (DML) quantification technique followed by nanoLC-MS/MS analysis. A total of 1096 unique proteins were identified and quantified, with 40.3 % (211/524) predicted as integral MPs with at least one transmembrane domain (TMD) found in the detergent phase, and 10 % (80/798) in the detergent-depleted phase. Among these, 62 proteins were shown to be significantly altered (p-value < 0.05), in AD versus control samples. In the detergent fraction, we found 10 hydrophobic transmembrane proteins containing up to 14 putative TMDs that were significantly up- or down-regulated in AD compared with control brains. Changes in four of these proteins, alpha-enolase (ENOA), lysosome-associated membrane glycoprotein 1 (LAMP1), 14-3-3 protein gamma (1433G), and sarcoplasmic/endoplasmic reticulum calcium ATPase2 (AT2A2) were validated by immunoblotting. Our results emphasize that separating hydrophobic MPs in CPE contributes to an increased understanding of the underlying molecular mechanisms in AD. Such knowledge can become useful for the development of novel disease biomarkers.

Keywords
Alzheimer's disease (AD), Cloud point extraction (CPE), Membrane proteins (MPs), Dimethyl labeling quantitative proteomics, Brain tissue
National Category
Geriatrics Analytical Chemistry
Identifiers
urn:nbn:se:uu:diva-246344 (URN)10.1007/s00216-014-8320-8 (DOI)000348436100002 ()25416231 (PubMedID)
Available from: 2015-03-10 Created: 2015-03-05 Last updated: 2019-04-29Bibliographically approved
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