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Paslawski, W., Zareba-Paslawska, J., Zhang, X., Holzl, K., Wadensten, H., Shariatgorji, M., . . . Svenningsson, P. (2019). alpha-synuclein-lipoprotein interactions and elevated ApoE level in cerebrospinal fluid from Parkinson's disease patients. Proceedings of the National Academy of Sciences of the United States of America, 116(30), 15226-15235
Open this publication in new window or tab >>alpha-synuclein-lipoprotein interactions and elevated ApoE level in cerebrospinal fluid from Parkinson's disease patients
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2019 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 30, p. 15226-15235Article in journal (Refereed) Published
Abstract [en]

The progressive accumulation, aggregation, and spread of alpha-synuclein (alpha SN) are common hallmarks of Parkinson's disease (PD) pathology. Moreover, numerous proteins interact with alpha SN species, influencing its toxicity in the brain. In the present study, we extended analyses of alpha SN-interacting proteins to cerebrospinal fluid (CSF). Using coimmunoprecipitation, followed by mass spectrometry, we found that alpha SN colocalize with apolipoproteins on lipoprotein vesicles. We confirmed these interactions using several methods, including the enrichment of lipoproteins with a recombinant alpha SN, and the subsequent uptake of prepared vesicles by human dopaminergic neuronal-like cells. Further, we report an increased level of ApoE in CSF from early PD patients compared with matched controls in 3 independent cohorts. Moreover, in contrast to controls, we observed the presence of ApoE-positive neuromelanin-containing dopaminergic neurons in substantia nigra of PD patients. In conclusion, the cooccurrence of alpha SN on lipoprotein vesicles, and their uptake by dopaminergic neurons along with an increase of ApoE in early PD, proposes a mechanism(s) for alpha SN spreading in the extracellular milieu of PD.

Place, publisher, year, edition, pages
NATL ACAD SCIENCES, 2019
Keywords
apolipoproteins, alpha-synuclein, Parkinson's disease, cerebrospinal fluid
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:uu:diva-391372 (URN)10.1073/pnas.1821409116 (DOI)000476715500067 ()31270237 (PubMedID)
Funder
Swedish Foundation for Strategic Research EU, European Research CouncilSwedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2019-09-24 Created: 2019-09-24 Last updated: 2019-09-24Bibliographically approved
Shariatgorji, M., Nilsson, A., Fridjonsdottir, E., Vallianatou, T., Källbäck, P., Katan, L., . . . Andrén, P. E. (2019). Comprehensive mapping of neurotransmitter networks by MALDI-MS imaging. Nature Methods, 16(10), 1021-1028
Open this publication in new window or tab >>Comprehensive mapping of neurotransmitter networks by MALDI-MS imaging
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2019 (English)In: Nature Methods, ISSN 1548-7091, E-ISSN 1548-7105, Vol. 16, no 10, p. 1021-1028Article in journal (Refereed) Published
Abstract [en]

We present a mass spectrometry imaging (MSI) approach for the comprehensive mapping of neurotransmitter networks in specific brain regions. Our fluoromethylpyridinium-based reactive matrices facilitate the covalent charge-tagging of molecules containing phenolic hydroxyl and/or primary or secondary amine groups, including dopaminergic and serotonergic neurotransmitters and their associated metabolites. These matrices improved the matrix-assisted laser desorption/ionization (MALDI)-MSI detection limit toward low-abundance neurotransmitters and facilitated the simultaneous imaging of neurotransmitters in fine structures of the brain at a lateral resolution of 10 mu m. We demonstrate strategies for the identification of unknown molecular species using the innate chemoselectivity of the reactive matrices and the unique isotopic pattern of a brominated reactive matrix. We illustrate the capabilities of the developed method on Parkinsonian brain samples from human post-mortem tissue and animal models. The direct imaging of neurotransmitter systems provides a method for exploring how various neurological diseases affect specific brain regions through neurotransmitter modulation.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Analytical Chemistry
Identifiers
urn:nbn:se:uu:diva-395725 (URN)10.1038/s41592-019-0551-3 (DOI)000488225900033 ()31548706 (PubMedID)
Funder
Swedish Foundation for Strategic Research , RIF14-0078EU, FP7, Seventh Framework Programme, 607517Swedish Research Council, 2018-03320Swedish Research Council, 2018-05501Swedish Research Council, 2018-05133
Available from: 2019-10-24 Created: 2019-10-24 Last updated: 2019-10-24Bibliographically approved
Sugiyama, E., Guerrini, M. M., Honda, K., Hattori, Y., Abe, M., Källback, P., . . . Sugiura, Y. (2019). Detection of a High-Turnover Serotonin Circuit in the Mouse Brain Using Mass Spectrometry Imaging. ISCIENCE, 20, 359-+
Open this publication in new window or tab >>Detection of a High-Turnover Serotonin Circuit in the Mouse Brain Using Mass Spectrometry Imaging
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2019 (English)In: ISCIENCE, ISSN 2589-0042, Vol. 20, p. 359-+Article in journal (Refereed) Published
Abstract [en]

Monoamine neurotransmitters are released by specialized neurons regulating behavioral, motor, and cognitive functions. Although the localization of monoaminergic neurons in the brain is well known, the distribution and kinetics of monoamines remain unclear. Here, we generated a murine brain atlas of serotonin (5-HT), dopamine (DA), and norepinephrine (NE) levels using mass spectrometry imaging (MSI). We found several nuclei rich in both 5-HT and a catecholamine (DA or NE) and identified the paraventricular nucleus of the thalamus (PVT), where 5-HT and NE are co-localized. The analysis of 5-HT fluctuations in response to acute tryptophan depletion and infusion of isotope-labeled tryptophan in vivo revealed a close kinetic association between the raphe nuclei, PVT, and amygdala but not the other nuclei. Our findings imply the existence of a highly dynamic 5-HT-mediated raphe to PVT pathway that likely plays a role in the brain monoamine system.

Place, publisher, year, edition, pages
CELL PRESS, 2019
National Category
Neurosciences Neurology
Identifiers
urn:nbn:se:uu:diva-397301 (URN)10.1016/j.isci.2019.09.036 (DOI)000493388000028 ()31614319 (PubMedID)
Funder
Swedish Research Council, 2018-03320Swedish Research Council, 2018-05501
Available from: 2019-11-25 Created: 2019-11-25 Last updated: 2019-11-25Bibliographically approved
Vallianatou, T., Shariatgorji, M., Nilsson, A., Fridjonsdottir, E., Källback, P., Schintu, N., . . . Andrén, P. E. (2019). Molecular imaging identifies age-related attenuation of acetylcholine in retrosplenial cortex in response to acetylcholinesterase inhibition. Neuropsychopharmacology, 44, 2091-2098
Open this publication in new window or tab >>Molecular imaging identifies age-related attenuation of acetylcholine in retrosplenial cortex in response to acetylcholinesterase inhibition
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2019 (English)In: Neuropsychopharmacology, ISSN 0893-133X, Vol. 44, p. 2091-2098Article in journal (Refereed) Published
Abstract [en]

The neurotransmitter of the cholinergic system, acetylcholine plays a major role in the brain's cognitive function and is involved in neurodegenerative disorders. Here, we present age-related alterations of acetylcholine levels after administration of the acetylcholinesterase inhibitor drug tacrine in normal mice. Using a quantitative, robust and molecular-specific mass spectrometry imaging method we found that tacrine administration significantly raised acetylcholine levels in most areas of sectioned mice brains, inter alia the striatum, hippocampus and cortical areas. However, acetylcholine levels in retrosplenial cortex were significantly lower in 14-month-old than in 12-week-old animals following its administration, indicating that normal aging affects the cholinergic system's responsivity. This small brain region is interconnected with an array of brain networks and is involved in numerous cognitive tasks. Simultaneous visualization of distributions of tacrine and its hydroxylated metabolites in the brain revealed a significant decrease in levels of the metabolites in the 14-month-old mice. The results highlight strengths of the imaging technique to simultaneously investigate multiple molecular species and the drug-target effects in specific regions of the brain. The proposed approach has high potential in studies of neuropathological conditions and responses to neuroactive treatments.

Keywords
mass spectrometry imaging, acetylcholine, retrosplenial cortex, tacrine, aging
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-392312 (URN)10.1038/s41386-019-0397-5 (DOI)000490174900013 ()31009936 (PubMedID)
Funder
Swedish Research Council, 2018-03320Swedish Research Council, 2018-05501EU, FP7, Seventh Framework Programme, 607517The Swedish Brain FoundationSwedish Foundation for Strategic Research , RIF14-0078Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2019-09-02 Created: 2019-09-02 Last updated: 2019-11-08Bibliographically approved
Vallianatou, T., Strittmatter, N., Nilsson, A., Shariatgorji, M., Hamm, G., Pereira, M., . . . Andrén, P. E. (2018). A mass spectrometry imaging approach for investigating how drug-drug interactions influence drug blood-brain barrier permeability. NeuroImage, 172, 808-816
Open this publication in new window or tab >>A mass spectrometry imaging approach for investigating how drug-drug interactions influence drug blood-brain barrier permeability
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2018 (English)In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 172, p. 808-816Article in journal (Refereed) Published
Abstract [en]

There is a high need to develop quantitative imaging methods capable of providing detailed brain localization information of several molecular species simultaneously. In addition, extensive information on the effect of the blood-brain barrier on the penetration, distribution and efficacy of neuroactive compounds is required. Thus, we have developed a mass spectrometry imaging method to visualize and quantify the brain distribution of drugs with varying blood-brain barrier permeability. With this approach, we were able to determine blood-brain barrier transport of different drugs and define the drug distribution in very small brain structures (e.g., choroid plexus) due to the high spatial resolution provided. Simultaneously, we investigated the effect of drug-drug interactions by inhibiting the membrane transporter multidrug resistance 1 protein. We propose that the described approach can serve as a valuable analytical tool during the development of neuroactive drugs, as it can provide physiologically relevant information often neglected by traditional imaging technologies.

Keywords
Mass spectrometry imaging, Blood-brain barrier, Drug-drug interactions, Elacridar, Loperamide, Propranolol
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-353358 (URN)10.1016/j.neuroimage.2018.01.013 (DOI)000430364100067 ()29329980 (PubMedID)
Funder
Swedish Research Council, 2013-3105]Swedish Research Council, 2014-6215]Swedish Foundation for Strategic Research , RIF14-0078]AstraZenecaEU, FP7, Seventh Framework Programme, 607517The Swedish Brain FoundationScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2018-06-12 Created: 2018-06-12 Last updated: 2019-09-02Bibliographically approved
Källback, P., Nilsson, A. & Andrén, P. E. (2018). A Space Efficient Direct Access Data Compression Approach for Mass Spectrometry Imaging. Analytical Chemistry, 90(6), 3676-3682
Open this publication in new window or tab >>A Space Efficient Direct Access Data Compression Approach for Mass Spectrometry Imaging
2018 (English)In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 90, no 6, p. 3676-3682Article in journal (Refereed) Published
Abstract [en]

Advances in mass spectrometry imaging that improve both spatial and mass resolution are resulting in increasingly larger data files that are difficult to handle with current software. We have developed a novel near-lossless compression method with data entropy reduction that reduces the file size significantly. The reduction in data size can be set at four different levels (coarse, medium, fine, and superfine) prior to running the data compression. This can be applied to spectra or spectrum-by-spectrum, or it can be applied to transpose arrays or array-by-array, to efficiently read the data without decompressing the whole data set. The results show that a compression ratio of up to 5.9:1 was achieved for data from commercial mass spectrometry software programs and 55:1 for data from our in-house developed mslQuant program. Comparing the average signals from regions of interest, the maximum deviation was 0.2% between compressed and uncompressed data sets with coarse accuracy for the data entropy reduction. In addition, when accessing the compressed data by selecting a random m/z value using mslQuant, the time to update an image on the computer screen was only slightly increased from 92 (+/- 32) ms (uncompressed) to 114 (+/- 13) ms (compressed). Furthermore, the compressed data can be stored on readily accessible servers for data evaluation without further data reprocessing. We have developed a space efficient, direct access data compression algorithm for mass spectrometry imaging, which can be used for various data-demanding mass spectrometry imaging applications.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
National Category
Pharmaceutical Sciences Analytical Chemistry
Identifiers
urn:nbn:se:uu:diva-328051 (URN)10.1021/acs.analchem.7b03188 (DOI)000428219600007 ()
Funder
Swedish Research Council, 521-2013-3105 621-2014-6215The Swedish Brain FoundationSwedish Foundation for Strategic Research , RIF14-0078Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2017-08-19 Created: 2017-08-19 Last updated: 2018-06-28Bibliographically approved
Li, L., Andrén, P. E. & Sweedler, J. V. (2018). Editorial and Review: 29th ASMS Sanibel Conference on Mass Spectrometry-Peptidomics: Bridging the Gap between Proteomics and Metabolomics by MS. Journal of the American Society for Mass Spectrometry, 29(5), 801-806
Open this publication in new window or tab >>Editorial and Review: 29th ASMS Sanibel Conference on Mass Spectrometry-Peptidomics: Bridging the Gap between Proteomics and Metabolomics by MS
2018 (English)In: Journal of the American Society for Mass Spectrometry, ISSN 1044-0305, E-ISSN 1879-1123, Vol. 29, no 5, p. 801-806Article in journal, Editorial material (Other academic) Published
National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-358106 (URN)10.1007/s13361-018-1939-5 (DOI)000431802500001 ()29623661 (PubMedID)
Available from: 2018-08-24 Created: 2018-08-24 Last updated: 2018-08-24Bibliographically approved
Slazak, B., Kapusta, M., Strömstedt, A. A., Slomka, A., Krychowiak, M., Shariatgorji, M., . . . Göransson, U. (2018). How Does the Sweet Violet (Viola odorata L.) Fight Pathogens and Pests - Cyclotides as a Comprehensive Plant Host Defense System. Frontiers in Plant Science, 9, Article ID 1296.
Open this publication in new window or tab >>How Does the Sweet Violet (Viola odorata L.) Fight Pathogens and Pests - Cyclotides as a Comprehensive Plant Host Defense System
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2018 (English)In: Frontiers in Plant Science, ISSN 1664-462X, E-ISSN 1664-462X, Vol. 9, article id 1296Article in journal (Refereed) Published
Abstract [en]

Cyclotides are cyclic plant polypeptides of 27-37 amino acid residues. They have been extensively studied in bioengineering and drug development contexts. However, less is known about the relevance of cyclotides for the plants producing them. The anti-insect larvae effects of kB1 and antibacterial activity of cyO2 suggest that cyclotides are a part of plant host defense. The sweet violet (Viola odorata L.) produces a wide array of cyclotides, including kB1 (kalata B1) and cyO2 (cycloviolacin O2), with distinct presumed biological roles. Here, we evaluate V. odorata cyclotides' potency against plant pathogens and their mode of action using bioassays, liposome experiments and immunogold labeling for transmission electron microscopy (TEM). We explore the link between the biological activity and distribution in plant generative, vegetative tissues and seeds, depicted by immunohistochemistry and matrix assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI). Cyclotides cyO2, cyO3, cyO13, and cyO19 are shown to have potent activity against model fungal plant pathogens (Fusarium oxysporum, F. graminearum, F. culmorum, Mycosphaerella fragariae, Botrytis cinerea) and fungi isolated from violets (Colletotrichum utrechtense and Alternaria alternata), with minimal inhibitory concentrations (MICs) ranging from 0.8 to 25 mu M. Inhibition of phytopathogenic bacteria - Pseudomonas syringae pv. syringae, Dickeya dadantii and Pectobacterium atrosepticum - is also observed with MIC = 25-100 mu M. A membrane-disrupting antifungal mode of action is shown. Finding cyO2 inside the fungal spore cells in TEM images may indicate that other, intracellular targets may be involved in the mechanism of toxicity. Fungi can not break down cyclotides in the course of days. varv A (kalata S) and kB1 show little potency against pathogenic fungi when compared with the tested cycloviolacins. cyO2, cyO3, cyO19 and kB1 are differentially distributed and found in tissues vulnerable to pathogen (epidermis, rizodermis, vascular bundles, protodermis, procambium, ovary walls, outer integuments) and pest ( ground tissues of leaf and petiole) attacks, respectively, indicating a link between the cyclotides' sites of accumulation and biological role. Cyclotides emerge as a comprehensive defense system in V. odorata, in which different types of peptides have specific targets that determine their distribution in plant tissues.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2018
Keywords
cyclotides, plant host defense, Violaceae, antimicrobial peptide, antifungal defense, MALDI-MSI, immunohistochemistry
National Category
Botany
Identifiers
urn:nbn:se:uu:diva-365299 (URN)10.3389/fpls.2018.01296 (DOI)000444243600001 ()30254654 (PubMedID)
Funder
Swedish Research Council, 621-2007-5167Swedish Research Council, 621-2014-6215Swedish Foundation for Strategic Research , RIF14-0078Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2018-11-13 Created: 2018-11-13 Last updated: 2018-11-13Bibliographically approved
Jacobsson, E., Andersson, H. S., Strand, M., Peigneur, S., Eriksson, C., Lodén, H., . . . Göransson, U. (2018). Peptide ion channel toxins from the bootlace worm, the longest animal on Earth. Scientific Reports, 8, Article ID 4596.
Open this publication in new window or tab >>Peptide ion channel toxins from the bootlace worm, the longest animal on Earth
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 4596Article in journal (Refereed) Published
Abstract [en]

Polypeptides from animal venoms have found important uses as drugs, pharmacological tools, and within biotechnological and agricultural applications. We here report a novel family of cystine knot peptides from nemertean worms, with potent activity on voltage-gated sodium channels. These toxins, named the alpha-nemertides, were discovered in the epidermal mucus of Lineus longissimus, the 'bootlace worm' known as the longest animal on earth. The most abundant peptide, the 31-residue long alpha-1, was isolated, synthesized, and its 3D NMR structure determined. Transcriptome analysis including 17 species revealed eight alpha-nemertides, mainly distributed in the genus Lineus. alpha-1 caused paralysis and death in green crabs (Carcinus maenas) at 1 mu g/kg (similar to 300 pmol/kg). It showed profound effect on invertebrate voltage-gated sodium channels (e.g. Blattella germanica Na(v)1) at low nanomolar concentrations. Strong selectivity for insect over human sodium channels indicates that a-nemertides can be promising candidates for development of bioinsecticidal agents.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-351585 (URN)10.1038/s41598-018-22305-w (DOI)000428029600001 ()29567943 (PubMedID)
Funder
Swedish Research Council, 2014-3327]
Available from: 2018-05-29 Created: 2018-05-29 Last updated: 2019-08-15Bibliographically approved
Swales, J. G., Dexter, A., Hamm, G., Nilsson, A., Strittmatter, N., Michopoulos, F., . . . Goodwin, R. J. A. (2018). Quantitation of Endogenous Metabolites in Mouse Tumors Using Mass-Spectrometry Imaging. Analytical Chemistry, 90(10), 6051-6058
Open this publication in new window or tab >>Quantitation of Endogenous Metabolites in Mouse Tumors Using Mass-Spectrometry Imaging
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2018 (English)In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 90, no 10, p. 6051-6058Article in journal (Refereed) Published
Abstract [en]

Described is a quantitative-mass-spectrometry-imaging (qMSI) methodology for the analysis of lactate and glutamate distributions in order to delineate heterogeneity among mouse tumor models used to support drug-discovery efficacy testing. We evaluate and report on preanalysis-stabilization methods aimed at improving the reproducibility and efficiency of quantitative assessments of endogenous molecules in tissues. Stability experiments demonstrate that optimum stabilization protocols consist of frozen-tissue embedding, post-tissue-sectioning desiccation, and storage at -80 degrees C of tissue sections sealed in vacuum-tight containers. Optimized stabilization protocols are used in combination with qMSI methodology for the absolute quantitation of lactate and glutamate in tumors, incorporating the use of two different stable-isotope-labeled versions of each analyte and spectral-clustering performed on each tissue section using k-means clustering to allow region-specific, pixel-by-pixel quantitation. Region-specific qMSI was used to screen different tumor models and identify a phenotype that has low lactate heterogeneity, which will enable accurate measurements of lactate modulation in future drug-discovery studies. We conclude that using optimized qMSI protocols, it is possible to quantify endogenous metabolites within tumors, and region-specific quantitation can provide valuable insight into tissue heterogeneity and the tumor microenvironment.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2018
National Category
Analytical Chemistry
Identifiers
urn:nbn:se:uu:diva-356451 (URN)10.1021/acs.analchem.7b05239 (DOI)000432478600013 ()29668267 (PubMedID)
Funder
Swedish Research Council, 2014-6215Swedish Foundation for Strategic Research , RIF14-0078AstraZenecaScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2018-08-01 Created: 2018-08-01 Last updated: 2018-08-01Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-4062-7743

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