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Kononenko, O., Galatenko, V., Andersson, M., Bazov, I., Watanabe, H., Zhou, X., . . . Bakalkin, G. (2017). Intra- and interregional coregulation of opioid genes: broken symmetry in spinal circuits. The FASEB Journal, 31(5), 1953-1963
Open this publication in new window or tab >>Intra- and interregional coregulation of opioid genes: broken symmetry in spinal circuits
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2017 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 31, no 5, p. 1953-1963Article in journal (Refereed) Published
Abstract [en]

Regulation of the formation and rewiring of neural circuits by neuropeptides may require coordinated production of these signaling molecules and their receptors that may be established at the transcriptional level. Here, we address this hypothesis by comparing absolute expression levels of opioid peptides with their receptors, the largest neuropeptide family, and by characterizing coexpression (transcriptionally coordinated) patterns of these genes. We demonstrated that expression patterns of opioid genes highly correlate within and across functionally and anatomically different areas. Opioid peptide genes, compared with their receptor genes, are transcribed at much greater absolute levels, which suggests formation of a neuropeptide cloud that covers the receptor-expressed circuits. Surprisingly, we found that both expression levels and the proportion of opioid receptors are strongly lateralized in the spinal cord, interregional coexpression patterns are side specific, and intraregional coexpression profiles are affected differently by left-and right-side unilateral body injury. We propose that opioid genes are regulated as interconnected components of the same molecular system distributed between distinct anatomic regions. The striking feature of this system is its asymmetric coexpression patterns, which suggest side-specific regulation of selective neural circuits by opioid neurohormones.

Keywords
neuropeptides, spinal cord, lateralization
National Category
Natural Sciences Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-314798 (URN)10.1096/fj.201601039R (DOI)000399195500017 ()28122917 (PubMedID)
Funder
Swedish Research CouncilForte, Swedish Research Council for Health, Working Life and WelfareSwedish Research Council FormasSwedish InstituteThe Swedish Brain Foundation
Note

De 3 första författarna delar förstaförfattarskapet.

Available from: 2017-02-06 Created: 2017-02-06 Last updated: 2017-05-23Bibliographically approved
Fex Svenningsen, Å., Löring, S., Sørensen, A. L., Huynh, H. U., Hjæresen, S., Martin, N., . . . Benedikz, E. (2017). Macrophage migration inhibitory factor (MIF) modulates trophic signaling through interaction with serine protease HTRA1. Cellular and Molecular Life Sciences (CMLS), 24, 4561-4572
Open this publication in new window or tab >>Macrophage migration inhibitory factor (MIF) modulates trophic signaling through interaction with serine protease HTRA1
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2017 (English)In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 24, p. 4561-4572Article in journal (Refereed) Published
Abstract [en]

Macrophage migration inhibitory factor (MIF), a small conserved protein, is abundant in the immune- and central nervous system (CNS). MIF has several receptors and binding partners that can modulate its action on a cellular level. It is upregulated in neurodegenerative diseases and cancer although its function is far from clear. Here, we report the finding of a new binding partner to MIF, the serine protease HTRA1. This enzyme cleaves several growth factors, extracellular matrix molecules and is implicated in some of the same diseases as MIF. We show that the function of the binding between MIF and HTRA1 is to inhibit the proteolytic activity of HTRA1, modulating the availability of molecules that can change cell growth and differentiation. MIF is therefore the first endogenous inhibitor ever found for HTRA1. It was found that both molecules were present in astrocytes and that the functional binding has the ability to modulate astrocytic activities important in development and disease of the CNS.

Keywords
HTRA1, MIF, Protein interaction, Yeast-2-hybrid
National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-330365 (URN)10.1007/s00018-017-2592-z (DOI)000414150400009 ()28726057 (PubMedID)
Funder
Swedish Research Council, M 2006-4268
Available from: 2017-09-28 Created: 2017-09-28 Last updated: 2018-02-07Bibliographically approved
Sui, P., Watanabe, H., Artemenko, K., Sun, W., Bakalkin, G., Andersson, M. & Bergquist, J. (2017). Neuropeptide imaging in rat spinal cord with MALDI-TOF MS: Method development for the application in pain-related disease studies. European journal of mass spectrometry, 23(3), 105-115
Open this publication in new window or tab >>Neuropeptide imaging in rat spinal cord with MALDI-TOF MS: Method development for the application in pain-related disease studies
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2017 (English)In: European journal of mass spectrometry, ISSN 1469-0667, E-ISSN 1751-6838, Vol. 23, no 3, p. 105-115Article in journal (Refereed) Published
Abstract [en]

Spinal cord as a connection between brain and peripheral nervous system is an essential material for studying neural transmission, especially in pain-related research. This study was the first to investigate pain-related neuropeptide distribution in rat spinal cord using a matrix-assisted laser desorption ionization-time of flight imaging mass spectrometry (MALDI TOF MS) approach. The imaging workflow was evaluated and showed that MALDI TOF MS provides efficient resolution and robustness for neuropeptide imaging in rat spinal cord tissue. The imaging result showed that in naive rat spinal cord the molecular distribution of haeme, phosphatidylcholine, substance P and thymosin beta 4 were well in line with histological features. Three groups of pain-related neuropeptides, which are cleaved from prodynorphin, proenkephalin and protachykinin-1 proteins were detected. All these neuropeptides were found predominantly localized in the dorsal spinal cord and each group had unique distribution pattern. This study set the stage for future MALDI TOF MS application to elucidate signalling mechanism of pain-related diseases in small animal models.

Keywords
Matrix-assisted laser desorption ionization-time of flight imaging mass spectrometry, neuropathic pain, neuropeptide imaging, rat spinal cord
National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-330364 (URN)10.1177/1469066717703272 (DOI)000405717700004 ()28657437 (PubMedID)
Funder
Swedish Research Council, 621-2011-4423, 2015-4870
Available from: 2017-09-28 Created: 2017-09-28 Last updated: 2018-01-13Bibliographically approved
Kononenko, O., Bazov, I., Watanabe, H., Gerashchenko, G., Dyachok, O., Verbeek, D. S., . . . Bakalkin, G. (2017). Opioid precursor protein isoform is targeted to the cell nuclei in the human brain. Biochimica et Biophysica Acta, 1861(2), 246-255
Open this publication in new window or tab >>Opioid precursor protein isoform is targeted to the cell nuclei in the human brain
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2017 (English)In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1861, no 2, p. 246-255Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Neuropeptide precursors are traditionally viewed as proteins giving rise to small neuropeptide molecules. Prodynorphin (PDYN) is the precursor protein to dynorphins, endogenous ligands for the κ-opioid receptor. Alternative mRNA splicing of neuropeptide genes may regulate cell- and tissue-specific neuropeptide expression and produce novel protein isoforms. We here searched for novel PDYN mRNA and their protein product in the human brain.

METHODS: Novel PDYN transcripts were identified using nested PCR amplification of oligo(dT) selected full-length capped mRNA. Gene expression was analyzed by qRT-PCR, PDYN protein by western blotting and confocal imaging, dynorphin peptides by radioimmunoassay. Neuronal nuclei were isolated using fluorescence-activated nuclei sorting (FANS) from postmortem human striatal tissue. Immunofluorescence staining and confocal microscopy was performed for human caudate nucleus.

RESULTS: Two novel human PDYN mRNA splicing variants were identified. Expression of one of them was confined to the striatum where its levels constituted up to 30% of total PDYN mRNA. This transcript may be translated into ∆SP-PDYN protein lacking 13 N-terminal amino acids, a fragment of signal peptide (SP). ∆SP-PDYN was not processed to mature dynorphins and surprisingly, was targeted to the cell nuclei in a model cellular system. The endogenous PDYN protein was identified in the cell nuclei in human striatum by western blotting of isolated neuronal nuclei, and by confocal imaging.

CONCLUSIONS AND GENERAL SIGNIFICANCE: High levels of alternatively spliced ∆SP-PDYN mRNA and nuclear localization of PDYN protein suggests a nuclear function for this isoform of the opioid peptide precursor in human striatum.

Keywords
Alternative splicing, Human brain, Neuropeptide precursor protein, Nuclear localization, Prodynorphin
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-316836 (URN)10.1016/j.bbagen.2016.11.002 (DOI)000392680200023 ()27838394 (PubMedID)
Funder
Swedish Research Council, K2014-62X-12190-19-5Swedish Research Council Formas, 2009-1709 259-2012-23
Note

Shared first authorship for Kononenko O., Bazov I.

Available from: 2017-03-07 Created: 2017-03-07 Last updated: 2017-11-29
Bivehed, E., Strömvall, R., Bergquist, J., Bakalkin, G. & Andersson, M. (2017). Region-specific bioconversion of dynorphin neuropeptide detected by in situ histochemistry and MALDI imaging mass spectrometry. Peptides, 87, 20-27
Open this publication in new window or tab >>Region-specific bioconversion of dynorphin neuropeptide detected by in situ histochemistry and MALDI imaging mass spectrometry
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2017 (English)In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 87, p. 20-27Article in journal (Refereed) Published
Abstract [en]

Brain region-specific expression of proteolytic enzymes can control the biological activity of endogenous neuropeptides and has recently been targeted for the development of novel drugs, for neuropathic pain, cancer, and Parkinson's disease. Rapid and sensitive analytical methods to profile modulators of enzymatic activity are important for finding effective inhibitors with high therapeutic value. Combination of in situ enzyme histochemistry with MALDI imaging mass spectrometry allowed developing a highly sensitive method for analysis of brain-area specific neuropeptide conversion of synthetic and endogenous neuropeptides, and for selection of peptidase inhibitors that differentially target conversion enzymes at specific anatomical sites. Conversion and degradation products of Dynorphin B as model neuropeptide and effects of peptidase inhibitors applied to native brain tissue sections were analyzed at different brain locations. Synthetic dynorphin B (2 pmol) was found to be converted to the N-terminal fragments on brain sections whereas fewer C-terminal fragments were detected. N-ethylmaleimide (NEM), a non-selective inhibitor of cysteine peptidases, almost completely blocked the conversion of dynorphin B to dynorphin B(1-6; Leu-Enk-Arg), (1-9), (2-13), and (7-13). Proteinase inhibitor cocktail, and also incubation with acetic acid displayed similar results. Bioconversion of synthetic dynorphin B was region-specific producing dynorphin B(1-7) in the cortex and dynorphin B (2-13) in the striatum. Enzyme inhibitors showed region-and enzyme-specific inhibition of dynorphin bioconversion. Both phosphoramidon (inhibitor of the known dynorphin converting enzyme neprilysin) and opiorphin (inhibitor of neprilysin and aminopeptidase N) blocked cortical bioconversion to dynorphin B(1-7), wheras only opiorphin blocked striatal bioconversion to dynorphin B(2-13). This method may impact the development of novel therapies with aim to strengthen the effects of endogenous neuropeptides under pathological conditions such as chronic pain. Combining histochemistry and MALDI imaging MS is a powerful and sensitive tool for the study of inhibition of enzyme activity directly in native tissue sections. (C) 2016 The Authors. Published by Elsevier Inc.

Keywords
Neuropeptide, Dynorphin, Bioconversion, Enzyme, Enzyme inhibitor, Histochemistry, MALDI imaging mass spectrometry, Mass spectrometry, Parkinson's disease, Neuropathic pain
National Category
Pharmaceutical Sciences Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-316129 (URN)10.1016/j.peptides.2016.11.006 (DOI)000392684000003 ()27840228 (PubMedID)
Available from: 2017-03-10 Created: 2017-03-10 Last updated: 2018-01-13Bibliographically approved
Bergman, H.-M., Lundin, E., Andersson, M. & Lanekoff, I. (2016). Quantitative mass spectrometry imaging of small-molecule neurotransmitters in rat brain tissue sections using nanospray desorption electrospray ionization. The Analyst, 141(12), 3686-3695
Open this publication in new window or tab >>Quantitative mass spectrometry imaging of small-molecule neurotransmitters in rat brain tissue sections using nanospray desorption electrospray ionization
2016 (English)In: The Analyst, ISSN 0003-2654, E-ISSN 1364-5528, Vol. 141, no 12, p. 3686-3695Article in journal (Refereed) Published
Abstract [en]

Small molecule neurotransmitters are essential for the function of the nervous system, and neurotransmitter imbalances are often connected to neurological disorders. The ability to quantify such imbalances is important to provide insights into the biochemical mechanisms underlying the disorder. This proof-of-principle study presents online quantification of small molecule neurotransmitters, specifically acetylcholine, γ-aminobutyric acid (GABA) and glutamate, in rat brain tissue sections using nanospray desorption electrospray ionization (nano-DESI) mass spectrometry imaging. By incorporating deuterated internal standards in the nano-DESI solvent we show identification, accurate mapping, and quantification of these small neurotransmitters in rat brain tissue without introducing any additional sample preparation steps. We find that GABA is about twice as abundant in the medial septum-diagonal band complex (MSDB) as in the cortex, while glutamate is about twice as abundant in the cortex as compared to the MSDB. The study shows that nano-DESI is well suited for imaging of small molecule neurotransmitters in health and disease.

National Category
Analytical Chemistry
Identifiers
urn:nbn:se:uu:diva-281314 (URN)10.1039/c5an02620b (DOI)000378942900021 ()26859000 (PubMedID)
Funder
Swedish Research Council, VR 621-2013-4231Swedish Foundation for Strategic Research , SSF ICA-6
Available from: 2016-03-22 Created: 2016-03-22 Last updated: 2018-11-29
Schweizer, N., Viereckel, T., Smith-Anttila, C. J. A., Nordenankar, K., Arvidsson, E., Mahmoudi, S., . . . Wallén-Mackenzie, Å. (2016). Reduced Vglut2/Slc17a6 Gene Expression Levels throughout the Mouse Subthalamic Nucleus Cause Cell Loss and Structural Disorganization Followed by Increased Motor Activity and Decreased Sugar Consumption. ENEURO, 3(5), Article ID UNSP e0264.
Open this publication in new window or tab >>Reduced Vglut2/Slc17a6 Gene Expression Levels throughout the Mouse Subthalamic Nucleus Cause Cell Loss and Structural Disorganization Followed by Increased Motor Activity and Decreased Sugar Consumption
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2016 (English)In: ENEURO, ISSN 2373-2822, Vol. 3, no 5, article id UNSP e0264Article in journal (Refereed) Published
Abstract [en]

The subthalamic nucleus (STN) plays a central role in motor, cognitive, and affective behavior. Deep brain stimulation (DBS) of the STN is the most common surgical intervention for advanced Parkinson's disease (PD), and STN has lately gained attention as target for DBS in neuropsychiatric disorders, including obsessive compulsive disorder, eating disorders, and addiction. Animal studies using STN-DBS, lesioning, or inactivation of STN neurons have been used extensively alongside clinical studies to unravel the structural organization, circuitry, and function of the STN. Recent studies in rodent STN models have exposed different roles for STN neurons in reward-related functions. We have previously shown that the majority of STN neurons express the vesicular glutamate transporter 2 gene (Vglut2/Slc17a6) and that reduction of Vglut2 mRNA levels within the STN of mice [conditional knockout (cKO)] causes reduced postsynaptic activity and behavioral hyperlocomotion. The cKO mice showed less interest in fatty rewards, which motivated analysis of reward-response. The current results demonstrate decreased sugar consumption and strong rearing behavior, whereas biochemical analyses show altered dopaminergic and peptidergic activity in the striatum. The behavioral alterations were in fact correlated with opposite effects in the dorsal versus the ventral striatum. Significant cell loss and disorganization of the STN structure was identified, which likely accounts for the observed alterations. Rare genetic variants of the human VGLUT2 gene exist, and this study shows that reduced Vglut2/Slc17a6 gene expression levels exclusively within the STN of mice is sufficient to cause strong modifications in both the STN and the mesostriatal dopamine system.

Keywords
dopamine, dynorphin, glutamate, rearing, reward, self-administration
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-315932 (URN)10.1523/ENEURO.0264-16.2016 (DOI)000391930400042 ()
Funder
Swedish Research Council, Vetenskapsradet 2013-4657 2014-3804 2011-4423 2015-4870 2012-2304The Swedish Brain FoundationÅke Wiberg Foundation
Available from: 2017-02-22 Created: 2017-02-22 Last updated: 2017-09-05Bibliographically approved
Karlsson, O., Bergquist, J. & Andersson, M. (2014). Quality measures of imaging mass spectrometry aids in revealing long-term striatal protein changes induced by neonatal exposure to the cyanobacterial toxin β-N-methylamino-L-alanine (BMAA). Molecular & Cellular Proteomics, 13, 93-104
Open this publication in new window or tab >>Quality measures of imaging mass spectrometry aids in revealing long-term striatal protein changes induced by neonatal exposure to the cyanobacterial toxin β-N-methylamino-L-alanine (BMAA)
2014 (English)In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 13, p. 93-104Article in journal (Refereed) Published
Abstract [en]

Many pathological processes are not directly correlated to dramatic alterations in protein levels. The changes in local concentration of important proteins in a subset of cells or at specific loci is likely to play a significant role in the disease etiologies, but the precise location might be unknown or too small to be adequately sampled for the purpose of traditional proteomic techniques. In this respect, matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS) is a unique analytical method that combines analysis of multiple molecular species and their distribution in one single platform. As reproducibility is essential for successful biomarker discovery it is important to systemically assess data quality in biologically relevant MALDI IMS experiments. In the present study, we applied four simple tools to study the reproducibility for individual sections, within group variation and between group variations of data acquired from brain sections of 21 animals divided into three treatment groups. We also characterized protein changes in distinct regions of the striatum from six month-old rats treated neonatally (PND; postnatal days 9-10) with the cyanobacterial toxin β-N-methylamino-L-alanine (BMAA) that has been implicated in neurodegenerative diseases. The results showed that optimized experimental settings can render high quality MALDI IMS data with relatively low variation (14-15 %CV) that allows characterization of subtle changes in protein expression in various subregions of the brain. This was further exemplified by the dose-dependent reduction of MBP (myelin basic protein) in the caudate putamen and the nucleus accumbens of adult rats neonatally treated with BMAA (150 and 460 mg/kg). The MBP reduction was confirmed with immunohistochemistryand indicates that developmental exposure to BMAA may induce structural effects on axonal growth and/or directly on proliferation of oligodendrocytes and myelination, which might be important for the previously shown BMAA-induced long-term cognitive impairments.

National Category
Medical and Health Sciences Natural Sciences Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-210045 (URN)10.1074/mcp.M113.031435 (DOI)000329343000008 ()24126143 (PubMedID)
Available from: 2013-10-30 Created: 2013-10-30 Last updated: 2017-12-06Bibliographically approved
Ljungdahl, A., Hanrieder, J., Bergquist, J. & Andersson, M. (2013). Analysis of neuropeptides by MALDI imaging mass spectrometry. Methods in Molecular Biology, 1023, 121-136
Open this publication in new window or tab >>Analysis of neuropeptides by MALDI imaging mass spectrometry
2013 (English)In: Methods in Molecular Biology, ISSN 1064-3745, E-ISSN 1940-6029, Vol. 1023, p. 121-136Article in journal (Refereed) Published
Abstract [en]

Matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS) is one of the most effective tools for localizing small molecules and compounds directly in thin tissue sections. MALDI IMS should be used when the distribution of molecular species is not known and to localize changes due to a disease process or a treatment. In recent years it has become increasingly clear that many pathological processes are not readily correlated to dramatic changes in protein levels. MALDI IMS can aid the localization of areas where the cellular concentration of proteins may be high enough to play an important biological role, but when the precise location is unknown. Here, we present a MALDI IMS protocol and data analysis of molecular imaging of multiple rat brain sections.

National Category
Neurosciences
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-212977 (URN)10.1007/978-1-4614-7209-4_7 (DOI)23765622 (PubMedID)
Funder
Swedish Research Council
Available from: 2013-12-17 Created: 2013-12-17 Last updated: 2018-01-11Bibliographically approved
Hanrieder, J., Ekegren, T., Andersson, M. & Bergquist, J. (2013). MALDI Imaging of Post Mortem Human Spinal Cord in Amyotrophic Lateral Sclerosis. Journal of Neurochemistry, 124(5), 695-707
Open this publication in new window or tab >>MALDI Imaging of Post Mortem Human Spinal Cord in Amyotrophic Lateral Sclerosis
2013 (English)In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 124, no 5, p. 695-707Article in journal (Refereed) Published
Abstract [en]

Amyotrophic lateral sclerosis (ALS) is a devastating, rapidly progressing disease of the central nervous system that is characterized by motor neuron degeneration in the brain stem and the spinal cord. Matrix assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) is an emerging powerful technique that allows for spatially resolved, comprehensive and specific characterization of molecular species in situ. In this study we report for the first time, MALDI imaging-based spatial protein profiling and relative quantification of post mortem human spinal cord samples obtained from ALS patients and controls. In normal spinal cord, protein distribution patterns were well in line with histological features. For example, thymosin beta 4, ubiquitin, histone proteins, acyl CoA binding protein, and macrophage inhibitory factor were predominantly localized to the grey matter. Furthermore, unsupervised statistics revealed a significant reduction of two protein species in ALS grey matter. One of these proteins (m/z 8451) corresponds to an endogenous truncated form of ubiquitin (Ubc 1-76), with both C-terminal glycine residues removed (Ubc-T/Ubc 1-74). This region-specific ubiquitin processing suggests a disease-related change in protease activity. These results highlight the importance of MALDI IMS as a versatile approach to elucidate molecular mechanisms of neurodegenerative diseases.

Keywords
amyotrophic lateral sclerosis, imaging mass spectrometry, matrix-assisted laser desorption/ionization, post-mortem spinal cord, tissue imaging.
National Category
Natural Sciences
Research subject
Biochemistry
Identifiers
urn:nbn:se:uu:diva-182909 (URN)10.1111/jnc.12019 (DOI)000315105000012 ()
Available from: 2012-10-18 Created: 2012-10-18 Last updated: 2017-12-07Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-1450-8046

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