28710
2022
eng
13
article
1
--
2022-09-07
--
Shaped by leaky ER: Homeostatic Ca\(^{2+}\) fluxes
At any moment in time, cells coordinate and balance their calcium ion (Ca\(^{2+}\)) fluxes. The term ‘Ca\(^{2+}\) homeostasis’ suggests that balancing resting Ca2+ levels is a rather static process. However, direct ER Ca\(^{2+}\) imaging shows that resting Ca\(^{2+}\) levels are maintained by surprisingly dynamic Ca\(^{2+}\) fluxes between the ER Ca\(^{2+}\) store, the cytosol, and the extracellular space. The data show that the ER Ca\(^{2+}\) leak, continuously fed by the high-energy consuming SERCA, is a fundamental driver of resting Ca\(^{2+}\) dynamics. Based on simplistic Ca\(^{2+}\) toolkit models, we discuss how the ER Ca\(^{2+}\) leak could contribute to evolutionarily conserved Ca\(^{2+}\) phenomena such as Ca\(^{2+}\) entry, ER Ca\(^{2+}\) release, and Ca\(^{2+}\) oscillations.
Frontiers in Physiology
1664-042X
10.3389/fphys.2022.972104
urn:nbn:de:bvb:20-opus-287102
2022-09-21T08:42:19+00:00
sword
swordwue
attachment; filename=deposit.zip
c94c1be964dc2cb2bac64ee8586d58d9
Frontiers in Physiology (2022) 13:972104. doi: 10.3389/fphys.2022.972104
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Annemarie Schulte
Robert Blum
eng
uncontrolled
Ca2+ homeostasis
eng
uncontrolled
Ca2+ ion analysis
eng
uncontrolled
ER Ca2+ store
eng
uncontrolled
ER Ca2+ imaging
eng
uncontrolled
SERCA
eng
uncontrolled
store-operated Ca2+ entry
eng
uncontrolled
Ca2+ leak
eng
uncontrolled
Ca2+ oscillation
Medizin und Gesundheit
open_access
Neurologische Klinik und Poliklinik
Klinik und Poliklinik für Anästhesiologie (ab 2004)
Import
Förderzeitraum 2022
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/28710/fphys-13-972104.pdf
26523
2021
eng
1237–1250
9
99
article
1
--
--
--
Selective blood-nerve barrier leakiness with claudin-1 and vessel-associated macrophage loss in diabetic polyneuropathy
Diabetic polyneuropathy (DPN) is the most common complication in diabetes and can be painful in up to 26% of all diabetic patients. Peripheral nerves are shielded by the blood-nerve barrier (BNB) consisting of the perineurium and endoneurial vessels. So far, there are conflicting results regarding the role and function of the BNB in the pathophysiology of DPN. In this study, we analyzed the spatiotemporal tight junction protein profile, barrier permeability, and vessel-associated macrophages in Wistar rats with streptozotocin-induced DPN. In these rats, mechanical hypersensitivity developed after 2 weeks and loss of motor function after 8 weeks, while the BNB and the blood-DRG barrier were leakier for small, but not for large molecules after 8 weeks only. The blood-spinal cord barrier remained sealed throughout the observation period. No gross changes in tight junction protein or cytokine expression were observed in all barriers to blood. However, expression of Cldn1 mRNA in perineurium was specifically downregulated in conjunction with weaker vessel-associated macrophage shielding of the BNB. Our results underline the role of specific tight junction proteins and BNB breakdown in DPN maintenance and differentiate DPN from traumatic nerve injury. Targeting claudins and sealing the BNB could stabilize pain and prevent further nerve damage.
Journal of Molecular Medicine
10.1007/s00109-021-02091-1
urn:nbn:de:bvb:20-opus-265237
publish
Journal of Molecular Medicine 2021, 99(9):1237–1250. DOI: 10.1007/s00109-021-02091-1
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Adel Ben-Kraiem
Reine-Solange Sauer
Carla Norwig
Maria Popp
Anna-Lena Bettenhausen
Mariam Sobhy Atalla
Alexander Brack
Robert Blum
Kathrin Doppler
Heike Lydia Rittner
eng
uncontrolled
macrophages
eng
uncontrolled
neuropathy
eng
uncontrolled
barrier
eng
uncontrolled
pain
Medizin und Gesundheit
open_access
Institut für Klinische Neurobiologie
Neurologische Klinik und Poliklinik
Klinik und Poliklinik für Anästhesiologie (ab 2004)
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/26523/Ben-Kraiem_Molecular.pdf
28502
2019
eng
1
21
article
1
--
2019-12-31
--
Regional differences in tight junction protein expression in the blood−DRG barrier and their alterations after nerve traumatic injury in rats
The nervous system is shielded by special barriers. Nerve injury results in blood–nerve barrier breakdown with downregulation of certain tight junction proteins accompanying the painful neuropathic phenotype. The dorsal root ganglion (DRG) consists of a neuron-rich region (NRR, somata of somatosensory and nociceptive neurons) and a fibre-rich region (FRR), and their putative epi-/perineurium (EPN). Here, we analysed blood–DRG barrier (BDB) properties in these physiologically distinct regions in Wistar rats after chronic constriction injury (CCI). Cldn5, Cldn12, and Tjp1 (rats) mRNA were downregulated 1 week after traumatic nerve injury. Claudin-1 immunoreactivity (IR) found in the EPN, claudin-19-IR in the FRR, and ZO-1-IR in FRR-EPN were unaltered after CCI. However, laser-assisted, vessel specific qPCR, and IR studies confirmed a significant loss of claudin-5 in the NRR. The NRR was three-times more permeable compared to the FRR for high and low molecular weight markers. NRR permeability was not further increased 1-week after CCI, but significantly more CD68\(^+\) macrophages had migrated into the NRR. In summary, NRR and FRR are different in naïve rats. Short-term traumatic nerve injury leaves the already highly permeable BDB in the NRR unaltered for small and large molecules. Claudin-5 is downregulated in the NRR. This could facilitate macrophage invasion, and thereby neuronal sensitisation and hyperalgesia. Targeting the stabilisation of claudin-5 in microvessels and the BDB barrier could be a future approach for neuropathic pain therapy.
International Journal of Molecular Sciences
1422-0067
10.3390/ijms21010270
urn:nbn:de:bvb:20-opus-285029
2022-09-05T12:27:52+00:00
sword
swordwue
attachment; filename=deposit.zip
6819f859e464a6d2744ad93046b4f17b
International Journal of Molecular Sciences (2020) 21:1, 270. https://doi.org/10.3390/ijms21010270
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Thomas J. Lux
Xiawei Hu
Adel Ben-Kraiem
Robert Blum
Jeremy Tsung-Chieh Chen
Heike L. Rittner
eng
uncontrolled
tight junction
eng
uncontrolled
claudin-5
eng
uncontrolled
neuropathic pain
eng
uncontrolled
nerve injury
eng
uncontrolled
dorsal root ganglion
Medizin und Gesundheit
open_access
Institut für Klinische Neurobiologie
Klinik und Poliklinik für Anästhesiologie (ab 2004)
Import
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/28502/ijms-21-00270-v2.pdf
17004
2017
eng
678
8
article
1
2018-10-25
--
--
Plekhg5-regulated autophagy of synaptic vesicles reveals a pathogenic mechanism in motoneuron disease
Autophagy-mediated degradation of synaptic components maintains synaptic homeostasis but also constitutes a mechanism of neurodegeneration. It is unclear how autophagy of synaptic vesicles and components of presynaptic active zones is regulated. Here, we show that Pleckstrin homology containing family member 5 (Plekhg5) modulates autophagy of synaptic vesicles in axon terminals of motoneurons via its function as a guanine exchange factor for Rab26, a small GTPase that specifically directs synaptic vesicles to preautophagosomal structures. Plekhg5 gene inactivation in mice results in a late-onset motoneuron disease, characterized by degeneration of axon terminals. Plekhg5-depleted cultured motoneurons show defective axon growth and impaired autophagy of synaptic vesicles, which can be rescued by constitutively active Rab26. These findings define a mechanism for regulating autophagy in neurons that specifically targets synaptic vesicles. Disruption of this mechanism may contribute to the pathophysiology of several forms of motoneuron disease.
Nature Communications
10.1038/s41467-017-00689-z
29084947
urn:nbn:de:bvb:20-opus-170048
Nature Communications 2017, 8:678. DOI: 10.1038/s41467-017-00689-z
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Patrick Lüningschrör
Beyenech Binotti
Benjamin Dombert
Peter Heimann
Angel Perez-Lara
Carsten Slotta
Nadine Thau-Habermann
Cora R. von Collenberg
Franziska Karl
Markus Damme
Arie Horowitz
Isabelle Maystadt
Annette Füchtbauer
Ernst-Martin Füchtbauer
Sibylle Jablonka
Robert Blum
Nurcan Üçeyler
Susanne Petri
Barbara Kaltschmidt
Reinhard Jahn
Christian Kaltschmidt
Michael Sendtner
eng
uncontrolled
autophagy
eng
uncontrolled
synaptic vesicles
eng
uncontrolled
Pleckstrin homology containing family member 5 (Plekhg5)
eng
uncontrolled
regulation
eng
uncontrolled
motoneuron disease
Medizin und Gesundheit
open_access
Institut für Klinische Neurobiologie
Neurologische Klinik und Poliklinik
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/17004/015_Luningschror_Nature-Communications.pdf
22343
2021
eng
11
article
1
--
2021-01-25
--
Pain Control by Targeting Oxidized Phospholipids: Functions, Mechanisms, Perspectives
Within the lipidome oxidized phospholipids (OxPL) form a class of chemically highly reactive metabolites. OxPL are acutely produced in inflamed tissue and act as endogenous, proalgesic (pain-inducing) metabolites. They excite sensory, nociceptive neurons by activating transient receptor potential ion channels, specifically TRPA1 and TRPV1. Under inflammatory conditions, OxPL-mediated receptor potentials even potentiate the action potential firing rate of nociceptors. Targeting OxPL with D-4F, an apolipoprotein A-I mimetic peptide or antibodies like E06, specifically binding oxidized headgroups of phospholipids, can be used to control acute, inflammatory pain syndromes, at least in rodents. With a focus on proalgesic specificities of OxPL, this article discusses, how targeting defined substances of the epilipidome can contribute to mechanism-based therapies against primary and secondary chronic inflammatory or possibly also neuropathic pain.
Frontiers in Endocrinology
1664-2392
10.3389/fendo.2020.613868
urn:nbn:de:bvb:20-opus-223432
2021-02-08T06:18:20+00:00
sword
swordwue
attachment; filename=deposit.zip
7493d396723c4d6b1f447d533d2a47d7
Frontiers in Endocrinology 2021, 11:613868. doi: 10.3389/fendo.2020.613868
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Beatrice Oehler
Alexander Brack
Robert Blum
Heike L. Rittner
eng
uncontrolled
oxidized phospholipids
eng
uncontrolled
TRP channel
eng
uncontrolled
ion channel
eng
uncontrolled
analgesia
eng
uncontrolled
pain therapy
eng
uncontrolled
nociception
eng
uncontrolled
therapeutic antibody
eng
uncontrolled
mimetic peptide
Medizin und Gesundheit
open_access
Institut für Klinische Neurobiologie
Klinik und Poliklinik für Anästhesiologie (ab 2004)
Import
Förderzeitraum 2020
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/22343/fendo-11-613868.pdf
18823
2016
eng
93-110
1
132
article
1
2019-10-02
--
--
Neurofilament depletion improves microtubule dynamics via modulation of Stat3/stathmin signaling
In neurons, microtubules form a dense array within axons, and the stability and function of this microtubule network is modulated by neurofilaments. Accumulation of neurofilaments has been observed in several forms of neurodegenerative diseases, but the mechanisms how elevated neurofilament levels destabilize axons are unknown so far. Here, we show that increased neurofilament expression in motor nerves of pmn mutant mice, a model of motoneuron disease, causes disturbed microtubule dynamics. The disease is caused by a point mutation in the tubulin-specific chaperone E (Tbce) gene, leading to an exchange of the most C-terminal amino acid tryptophan to glycine. As a consequence, the TBCE protein becomes instable which then results in destabilization of axonal microtubules and defects in axonal transport, in particular in motoneurons. Depletion of neurofilament increases the number and regrowth of microtubules in pmn mutant motoneurons and restores axon elongation. This effect is mediated by interaction of neurofilament with the stathmin complex. Accumulating neurofilaments associate with stathmin in axons of pmn mutant motoneurons. Depletion of neurofilament by Nefl knockout increases Stat3-stathmin interaction and stabilizes the microtubules in pmn mutant motoneurons. Consequently, counteracting enhanced neurofilament expression improves axonal maintenance and prolongs survival of pmn mutant mice. We propose that this mechanism could also be relevant for other neurodegenerative diseases in which neurofilament accumulation and loss of microtubules are prominent features.
Acta Neuropathologica
10.1007/s00401-016-1564-y
urn:nbn:de:bvb:20-opus-188234
Acta Neuropathologica (2016) 132:1, 93-110. https://doi.org/10.1007/s00401-016-1564-y
259867
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Preeti Yadav
Bhuvaneish T. Selvaraj
Florian L. P. Bender
Marcus Behringer
Mehri Moradi
Rajeeve Sivadasan
Benjamin Dombert
Robert Blum
Esther Asan
Markus Sauer
Jean-Pierre Julien
Michael Sendtner
eng
uncontrolled
Amyotrophic-lateral-sclerosis
eng
uncontrolled
Transgenic mice
eng
uncontrolled
Mouse model
eng
uncontrolled
Alzheimers disease
eng
uncontrolled
Neurofilament
eng
uncontrolled
Progressive motor neuronopathy
eng
uncontrolled
Axonal transport
eng
uncontrolled
Intermediate filaments
eng
uncontrolled
Motoneuron disease
eng
uncontrolled
Lacking neurofilaments
eng
uncontrolled
Missense mutation
eng
uncontrolled
Axon degeneration
eng
uncontrolled
Microtubules
eng
uncontrolled
Stathmin
eng
uncontrolled
Stat3
Medizin und Gesundheit
open_access
Institut für Klinische Neurobiologie
Institut für Anatomie und Zellbiologie
Theodor-Boveri-Institut für Biowissenschaften
OpenAIRE
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/18823/Yadav_ActaNeuropathologica_2016.pdf
30060
2022
eng
194
210
101
article
1
--
--
--
Neurodegeneration by α-synuclein-specific T cells in AAV-A53T-α-synuclein Parkinson’s disease mice
Background
Antigen-specific neuroinflammation and neurodegeneration are characteristic for neuroimmunological diseases. In Parkinson’s disease (PD) pathogenesis, α-synuclein is a known culprit. Evidence for α-synuclein-specific T cell responses was recently obtained in PD. Still, a causative link between these α-synuclein responses and dopaminergic neurodegeneration had been lacking. We thus addressed the functional relevance of α-synuclein-specific immune responses in PD in a mouse model.
Methods
We utilized a mouse model of PD in which an Adeno-associated Vector 1/2 serotype (AAV1/2) expressing human mutated A53T-α-Synuclein was stereotactically injected into the substantia nigra (SN) of either wildtype C57BL/6 or Recombination-activating gene 1 (RAG1)\(^{-/-}\) mice. Brain, spleen, and lymph node tissues from different time points following injection were then analyzed via FACS, cytokine bead assay, immunohistochemistry and RNA-sequencing to determine the role of T cells and inflammation in this model. Bone marrow transfer from either CD4\(^{+}\)/CD8\(^{-}\), CD4\(^{-}\)/CD8\(^{+}\), or CD4\(^{+}\)/CD8\(^{+}\) (JHD\(^{-/-}\)) mice into the RAG-1\(^{-/-}\) mice was also employed. In addition to the in vivo studies, a newly developed A53T-α-synuclein-expressing neuronal cell culture/immune cell assay was utilized.
Results
AAV-based overexpression of pathogenic human A53T-α-synuclein in dopaminergic neurons of the SN stimulated T cell infiltration. RNA-sequencing of immune cells from PD mouse brains confirmed a pro-inflammatory gene profile. T cell responses were directed against A53T-α-synuclein-peptides in the vicinity of position 53 (68–78) and surrounding the pathogenically relevant S129 (120–134). T cells were required for α-synuclein-induced neurodegeneration in vivo and in vitro, while B cell deficiency did not protect from dopaminergic neurodegeneration.
Conclusions
Using T cell and/or B cell deficient mice and a newly developed A53T-α-synuclein-expressing neuronal cell culture/immune cell assay, we confirmed in vivo and in vitro that pathogenic α-synuclein peptide-specific T cell responses can cause dopaminergic neurodegeneration and thereby contribute to PD-like pathology.
Brain, Behavior, and Immunity
10.1016/j.bbi.2022.01.007
urn:nbn:de:bvb:20-opus-300600
@articleKarikari.2022, author = Karikari, Akua A. and McFleder, Rhonda L. and Ribechini, Eliana and Blum, Robert and Bruttel, Valentin and Knorr, Susanne and Gehmeyr, Mona and Volkmann, Jens and Brotchie, Jonathan M. and Ahsan, Fadhil and Haack, Beatrice and Monoranu, Camelia-Maria and Keber, Ursula and Yeghiazaryan, Rima and Pagenstecher, Axel and Heckel, Tobias and Bischler, Thorsten and Wischhusen, Jörg and Koprich, James B. and Lutz, Manfred B. and Ip, Chi Wang, year = 2022, title = Neurodegeneration by α-synuclein-specific T cells in AAV-A53T-α-synuclein Parkinson’s disease mice, pages = 194–210, volume = 101, journal = Brain, behavior, and immunity, doi = 10.1016/j.bbi.2022.01.007,
md5:73e3c75cb837706b2fb528d5dd4cd321
2023-01-20T07:12:58+00:00
/tmp/phpzVzRjL
bibtex
63ca3efa241d30.19864793
Brain, Behavior, and Immunity 2022, 101:194-210. DOI: 10.1016/j.bbi.2022.01.007
false
true
CC BY-NC-ND: Creative-Commons-Lizenz: Namensnennung, Nicht kommerziell, Keine Bearbeitungen 4.0 International
Akua A. Karikari
Rhonda L. McFleder
Eliana Ribechini
Robert Blum
Valentin Bruttel
Susanne Knorr
Mona Gehmeyr
Jens Volkmann
Jonathan M. Brotchie
Fadhil Ahsan
Beatrice Haack
Camelia-Maria Monoranu
Ursula Keber
Rima Yeghiazaryan
Axel Pagenstecher
Tobias Heckel
Thorsten Bischler
Jörg Wischhusen
James B. Koprich
Manfred B. Lutz
Chi Wang Ip
eng
uncontrolled
Parkinson’s disease
eng
uncontrolled
α-synuclein-specific T cells
eng
uncontrolled
neurodegeneration
Medizin und Gesundheit
open_access
Institut für Klinische Neurobiologie
Pathologisches Institut
Institut für Virologie und Immunbiologie
Neurologische Klinik und Poliklinik
Förderzeitraum 2022
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/30060/Brain_Karikari.pdf
25909
2021
eng
3
22
article
1
2022-03-03
--
--
Mesencephalic electrical stimulation reduces neuroinflammation after photothrombotic stroke in rats by targeting the cholinergic anti-inflammatory pathway
Inflammation is crucial in the pathophysiology of stroke and thus a promising therapeutic target. High-frequency stimulation (HFS) of the mesencephalic locomotor region (MLR) reduces perilesional inflammation after photothrombotic stroke (PTS). However, the underlying mechanism is not completely understood. Since distinct neural and immune cells respond to electrical stimulation by releasing acetylcholine, we hypothesize that HFS might trigger the cholinergic anti-inflammatory pathway via activation of the α7 nicotinic acetylcholine receptor (α7nAchR). To test this hypothesis, rats underwent PTS and implantation of a microelectrode into the MLR. Three hours after intervention, either HFS or sham-stimulation of the MLR was applied for 24 h. IFN-γ, TNF-α, and IL-1α were quantified by cytometric bead array. Choline acetyltransferase (ChAT)\(^+\) CD4\(^+\)-cells and α7nAchR\(^+\)-cells were quantified visually using immunohistochemistry. Phosphorylation of NFĸB, ERK1/2, Akt, and Stat3 was determined by Western blot analyses. IFN-γ, TNF-α, and IL-1α were decreased in the perilesional area of stimulated rats compared to controls. The number of ChAT\(^+\) CD4\(^+\)-cells increased after MLR-HFS, whereas the amount of α7nAchR\(^+\)-cells was similar in both groups. Phospho-ERK1/2 was reduced significantly in stimulated rats. The present study suggests that MLR-HFS may trigger anti-inflammatory processes within the perilesional area by modulating the cholinergic system, probably via activation of the α7nAchR.
International Journal of Molecular Sciences
10.3390/ijms22031254
urn:nbn:de:bvb:20-opus-259099
1422-0067
publish
International Journal of Molecular Sciences (2021) 22:3, 1254. https://doi.org/10.3390/ijms22031254
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Michael K. Schuhmann
Lena Papp
Guido Stoll
Robert Blum
Jens Volkmann
Felix Fluri
eng
uncontrolled
photothrombotic stroke
eng
uncontrolled
deep brain stimulation
eng
uncontrolled
mesencephalic locomotor region
eng
uncontrolled
neuroinflammation
eng
uncontrolled
choline acetyltransferase
eng
uncontrolled
alpha-7 nicotinic acetylcholine receptor
Medizin und Gesundheit
open_access
Institut für Klinische Neurobiologie
Neurologische Klinik und Poliklinik
Förderzeitraum 2021
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/25909/ijms-22-01254.pdf
18725
2016
eng
489-512
4
146
article
1
2019-09-12
--
--
Initial characterization of a Syap1 knock-out mouse and distribution of Syap1 in mouse brain and cultured motoneurons
Synapse-associated protein 1 (Syap1/BSTA) is the mammalian homologue of Sap47 (synapse-associated protein of 47 kDa) in Drosophila. Sap47 null mutant larvae show reduced short-term synaptic plasticity and a defect in associative behavioral plasticity. In cultured adipocytes, Syap1 functions as part of a complex that phosphorylates protein kinase B alpha/Akt1 (Akt1) at Ser\(^{473}\) and promotes differentiation. The role of Syap1 in the vertebrate nervous system is unknown. Here, we generated a Syap1 knock-out mouse and show that lack of Syap1 is compatible with viability and fertility. Adult knock-out mice show no overt defects in brain morphology. In wild-type brain, Syap1 is found widely distributed in synaptic neuropil, notably in regions rich in glutamatergic synapses, but also in perinuclear structures associated with the Golgi apparatus of specific groups of neuronal cell bodies. In cultured motoneurons, Syap1 is located in axons and growth cones and is enriched in a perinuclear region partially overlapping with Golgi markers. We studied in detail the influence of Syap1 knockdown and knockout on structure and development of these cells. Importantly, Syap1 knockout does not affect motoneuron survival or axon growth. Unexpectedly, neither knockdown nor knockout of Syap1 in cultured motoneurons is associated with reduced Ser\(^{473}\) or Thr\(^{308}\) phosphorylation of Akt. Our findings demonstrate a widespread expression of Syap1 in the mouse central nervous system with regionally specific distribution patterns as illustrated in particular for olfactory bulb, hippocampus, and cerebellum.
Histochemistry and Cell Biology
10.1007/s00418-016-1457-0
urn:nbn:de:bvb:20-opus-187258
Histochemistry and Cell Biology (2016) 146:4, 489-512. https://doi.org/10.1007/s00418-016-1457-0
312325
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Dominique Schmitt
Natalia Funk
Robert Blum
Esther Asan
Lill Andersen
Thomas Rülicke
Michael Sendtner
Erich Buchner
eng
uncontrolled
Protein kinase B
eng
uncontrolled
Spinal Muscular-arthropy
eng
uncontrolled
Rictor-mTOR complex
eng
uncontrolled
Neurotrophic factors
eng
uncontrolled
Plasma-membrane
eng
uncontrolled
Axon growth
eng
uncontrolled
SAP47 gene
eng
uncontrolled
Phosphorylation
eng
uncontrolled
Drosophilia
eng
uncontrolled
Cells
eng
uncontrolled
BSTA
eng
uncontrolled
Viability
eng
uncontrolled
Brain
eng
uncontrolled
Syap1 localization
eng
uncontrolled
Glutamatergic synapses
eng
uncontrolled
PKB/Akt phosphorylation
Medizin und Gesundheit
open_access
Institut für Klinische Neurobiologie
Institut für Anatomie und Zellbiologie
OpenAIRE
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/18725/Schmitt_HistochemistryAndCellBiology_2016.pdf
15853
2017
eng
5447
7
article
1
2018-03-06
--
--
Inflammatory pain control by blocking oxidized phospholipid-mediated TRP channel activation
Phospholipids occurring in cell membranes and lipoproteins are converted into oxidized phospholipids (OxPL) by oxidative stress promoting atherosclerotic plaque formation. Here, OxPL were characterized as novel targets in acute and chronic inflammatory pain. Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC) and its derivatives were identified in inflamed tissue by mass spectrometry and binding assays. They elicited calcium influx, hyperalgesia and induced pro-nociceptive peptide release. Genetic, pharmacological and mass spectrometric evidence in vivo as well as in vitro confirmed the role of transient receptor potential channels (TRPA1 and TRPV1) as OxPAPC targets. Treatment with the monoclonal antibody E06 or with apolipoprotein A-I mimetic peptide D-4F, capturing OxPAPC in atherosclerosis, prevented inflammatory hyperalgesia, and in vitro TRPA1 activation. Administration of D-4F or E06 to rats profoundly ameliorated mechanical hyperalgesia and inflammation in collagen-induced arthritis. These data reveal a clinically relevant role for OxPAPC in inflammation offering therapy for acute and chronic inflammatory pain treatment by scavenging OxPAPC.
Scientific Reports
10.1038/s41598-017-05348-3
urn:nbn:de:bvb:20-opus-158536
Scientific Reports 7:5447 (2017). DOI: : 10.1038/s41598-017-05348-3
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Beatrice Oehler
Katrin Kistner
Corinna Martin
Jürgen Schiller
Rafaela Mayer
Milad Mohammadi
Reine-Solange Sauer
Milos R. Filipovic
Francisco R. Nieto
Jan Kloka
Diana Pflücke
Kerstin Hill
Michael Schaefer
Marzia Malcangio
Peter W. Reeh
Alexander Brack
Robert Blum
Heike L. Rittner
eng
uncontrolled
chronic pain
eng
uncontrolled
ion channels in the nervous system
eng
uncontrolled
molecular medicine
eng
uncontrolled
pain
Medizin und Gesundheit
open_access
Institut für Klinische Neurobiologie
Klinik und Poliklinik für Anästhesiologie (ab 2004)
Förderzeitraum 2017
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/15853/Oehler_Scientific_Reports.pdf
11979
2014
eng
107
8
article
1
2015-10-05
--
--
High abundance of BDNF within glutamatergic presynapses of cultured hippocampal neurons
In the mammalian brain, the neurotrophin brain-derived neurotrophic factor (BDNF) has emerged as a key factor for synaptic refinement, plasticity and learning. Although BDNF-induced signaling cascades are well known, the spatial aspects of the synaptic BDNF localization remained unclear. Recent data provide strong evidence for an exclusive presynaptic location and anterograde secretion of endogenous BDNF at synapses of the hippocampal circuit. In contrast, various studies using BDNF overexpression in cultured hippocampal neurons support the idea that postsynaptic elements and other dendritic structures are the preferential sites of BDNF localization and release. In this study we used rigorously tested anti-BDNF antibodies and achieved a dense labeling of endogenous BDNF close to synapses. Confocal microscopy showed natural BDNF close to many, but not all glutamatergic synapses, while neither GABAergic synapses nor postsynaptic structures carried a typical synaptic BDNF label. To visualize the BDNF distribution within the fine structure of synapses, we implemented super resolution fluorescence imaging by direct stochastic optical reconstruction microscopy (dSTORM). Two-color dSTORM images of neurites were acquired with a spatial resolution of ~20 nm. At this resolution, the synaptic scaffold proteins Bassoon and Homer exhibit hallmarks of mature synapses and form juxtaposed bars, separated by a synaptic cleft. BDNF imaging signals form granule-like clusters with a mean size of ~60 nm and are preferentially found within the fine structure of the glutamatergic presynapse. Individual glutamatergic presynapses carried up to 90% of the synaptic BDNF immunoreactivity, and only a minor fraction of BDNF molecules was found close to the postsynaptic bars. Our data proof that hippocampal neurons are able to enrich and store high amounts of BDNF in small granules within the mature glutamatergic presynapse, at a principle site of synaptic plasticity.
Frontiers in Cellular Neuroscience
10.3389/fncel.2014.00107
1662-5102
urn:nbn:de:bvb:20-opus-119793
Frontiers in Cellular Neuroscience 8:107. doi:10.3389/fncel.2014.00107
Thomas Andreska
Sarah Aufmkolk
Markus Sauer
Robert Blum
eng
uncontrolled
hippocampal neurons
eng
uncontrolled
synapse structure
eng
uncontrolled
presynapse
eng
uncontrolled
synaptic localization
eng
uncontrolled
BDNF
Humanphysiologie
open_access
Institut für Klinische Neurobiologie
Theodor-Boveri-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/11979/056_Andreska_Frontieres_in_Cellular_Neuroscience.pdf
30124
2022
eng
22
article
1
--
--
--
Differences in stem cell marker and osteopontin expression in primary and recurrent glioblastoma
Background
Despite of a multimodal approach, recurrences can hardly be prevented in glioblastoma. This may be in part due to so called glioma stem cells. However, there is no established marker to identify these stem cells.
Methods
Paired samples from glioma patients were analyzed by immunohistochemistry for expression of the following stem cell markers: CD133, Musashi, Nanog, Nestin, octamer-binding transcription factor 4 (Oct4), and sex determining region Y-box 2 (Sox2). In addition, the expression of osteopontin (OPN) was investigated. The relative number of positively stained cells was determined. By means of Kaplan–Meier analysis, a possible association with overall survival by marker expression was investigated.
Results
Sixty tissue samples from 30 patients (17 male, 13 female) were available for analysis. For Nestin, Musashi and OPN a significant increase was seen. There was also an increase (not significant) for CD133 and Oct4. Patients with mutated Isocitrate Dehydrogenase-1/2 (IDH-1/2) status had a reduced expression for CD133 and Nestin in their recurrent tumors. Significant correlations were seen for CD133 and Nanog between OPN in the primary and recurrent tumor and between CD133 and Nestin in recurrent tumors. By confocal imaging we could demonstrate a co-expression of CD133 and Nestin within recurrent glioma cells. Patients with high CD133 expression had a worse prognosis (22.6 vs 41.1 months, p = 0.013). A similar trend was seen for elevated Nestin levels (24.9 vs 41.1 months, p = 0.08).
Conclusions
Most of the evaluated markers showed an increased expression in their recurrent tumor. CD133 and Nestin were associated with survival and are candidate markers for further clinical investigation.
Cancer Cell International
1475-2867
10.1186/s12935-022-02510-4
urn:nbn:de:bvb:20-opus-301240
@articlePolat.2022, author = Polat, Bülent and Wohlleben, Gisela and Kosmala, Rebekka and Lisowski, Dominik and Mantel, Frederick and Lewitzki, Victor and Löhr, Mario and Blum, Robert and Herud, Petra and Flentje, Michael and Monoranu, Camelia-Maria, year = 2022, title = Differences in stem cell marker and osteopontin expression in primary and recurrent glioblastoma, pages = 87, volume = 22, number = 1, issn = 1475-2867, journal = Cancer cell international, doi = 10.1186/s12935-022-02510-4,
md5:6fee05145cad368b23e5d189bbbc7e6a
2023-01-25T15:17:13+00:00
/tmp/phpIQumPa
bibtex
63d147f91a0936.81300131
Cancer Cell International (2022) 22:87. doi:10.1186/s12935-022-02510-4
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Bülent Polat
Gisela Wohlleben
Rebekka Kosmala
Dominik Lisowski
Frederick Mantel
Victor Lewitzki
Mario Löhr
Robert Blum
Petra Herud
Michael Flentje
Camelia-Maria Monoranu
eng
uncontrolled
Glioblastoma
eng
uncontrolled
Glioma stem cells
eng
uncontrolled
Osteopontin
eng
uncontrolled
CD133
eng
uncontrolled
Nestin
Medizin und Gesundheit
open_access
Neurochirurgische Klinik und Poliklinik
Klinik und Poliklinik für Strahlentherapie
Pathologisches Institut
Neurologische Klinik und Poliklinik
Förderzeitraum 2022
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/30124/s12935-022-02510-4.pdf
13258
2013
eng
51-56
1
7
article
1
2016-04-21
--
--
Cell-autonomous axon growth of young motoneurons is triggered by a voltage-gated sodium channel
Spontaneous electrical activity preceding synapse formation contributes to the precise regulation of neuronal development. Examining the origins of spontaneous activity revealed roles for neurotransmitters that depolarize neurons and activate ion channels. Recently, we identified a new molecular mechanism underlying fluctuations in spontaneous neuronal excitability. We found that embryonic motoneurons with a genetic loss of the low-threshold sodium channel Na\(_V\)1.9 show fewer fluctuations in intracellular calcium in axonal compartments and growth cones than wild-type littermates. As a consequence, axon growth of Na\(_V\)1.9-deficient motoneurons in cell culture is drastically reduced while dendritic growth and cell survival are not affected. Interestingly, Na\(_V\)1.9 function is observed under conditions that would hardly allow a ligand- or neurotransmitter-dependent depolarization. Thus, Na\(_V\)1.9 may serve as a cell-autonomous trigger for neuronal excitation. In this addendum, we discuss a model for the interplay between cell-autonomous local neuronal activity and local cytoskeleton dynamics in growth cone function.
Channels (Austin)
10.4161/chan.23153
urn:nbn:de:bvb:20-opus-132586
Channels 7:1, 51–56; DOI: 10.4161/chan.23153
Andrea Wetzel
Sibylle Jablonka
Robert Blum
eng
uncontrolled
spontaneous excitation
eng
uncontrolled
spinal muscular atrophy
eng
uncontrolled
axon growth
eng
uncontrolled
sodium channel
eng
uncontrolled
motoneurons
eng
uncontrolled
local protein synthesis
eng
uncontrolled
NaV1.9
Humanphysiologie
open_access
Institut für Klinische Neurobiologie
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/13258/145_Wetzel_Channels_(Austin).pdf
17031
2017
eng
307
11
article
1
2018-10-29
--
--
Cadherin-13 Deficiency Increases Dorsal Raphe 5-HT Neuron Density and Prefrontal Cortex Innervation in the Mouse Brain
Background: During early prenatal stages of brain development, serotonin (5-HT)-specific neurons migrate through somal translocation to form the raphe nuclei and subsequently begin to project to their target regions. The rostral cluster of cells, comprising the median and dorsal raphe (DR), innervates anterior regions of the brain, including the prefrontal cortex. Differential analysis of the mouse 5-HT system transcriptome identified enrichment of cell adhesion molecules in 5-HT neurons of the DR. One of these molecules, cadherin-13 (Cdh13) has been shown to play a role in cell migration, axon pathfinding, and synaptogenesis. This study aimed to investigate the contribution of Cdh13 to the development of the murine brain 5-HT system.
Methods: For detection of Cdh13 and components of the 5-HT system at different embryonic developmental stages of the mouse brain, we employed immunofluorescence protocols and imaging techniques, including epifluorescence, confocal and structured illumination microscopy. The consequence of CDH13 loss-of-function mutations on brain 5-HT system development was explored in a mouse model of Cdh13 deficiency.
Results: Our data show that in murine embryonic brain Cdh13 is strongly expressed on 5-HT specific neurons of the DR and in radial glial cells (RGCs), which are critically involved in regulation of neuronal migration. We observed that 5-HT neurons are intertwined with these RGCs, suggesting that these neurons undergo RGC-guided migration. Cdh13 is present at points of intersection between these two cell types. Compared to wildtype controls, Cdh13-deficient mice display increased cell densities in the DR at embryonic stages E13.5, E17.5, and adulthood, and higher serotonergic innervation of the prefrontal cortex at E17.5.
Conclusion: Our findings provide evidence for a role of CDH13 in the development of the serotonergic system in early embryonic stages. Specifically, we indicate that Cdh13 deficiency affects the cell density of the developing DR and the posterior innervation of the prefrontal cortex (PFC), and therefore might be involved in the migration, axonal outgrowth and terminal target finding of DR 5-HT neurons. Dysregulation of CDH13 expression may thus contribute to alterations in this system of neurotransmission, impacting cognitive function, which is frequently impaired in neurodevelopmental disorders including attention-deficit/hyperactivity and autism spectrum disorders.
Frontiers in Cellular Neuroscience
10.3389/fncel.2017.00307
29018333
urn:nbn:de:bvb:20-opus-170313
Frontiers in Cellular Neuroscience 2017, Volume 11, Article 307. DOI: 10.3389/fncel.2017.00307
602805
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Andrea Ferero
Olga Rivero
Sina Wäldchen
Hsing-Ping Ku
Dominik P. Kiser
Yvonne Gärtner
Laura S. Pennington
Jonas Waider
Patricia Gaspar
Charline Jansch
Frank Edenhofer
Thérèse J. Resink
Robert Blum
Markus Sauer
Klaus-Peter Lesch
eng
uncontrolled
serotonin
eng
uncontrolled
cadherin-13 (CDH13)
eng
uncontrolled
T-cadherin
eng
uncontrolled
neurodevelopment
eng
uncontrolled
psychiatric disorders
eng
uncontrolled
radial glia
eng
uncontrolled
dorsal raphe
eng
uncontrolled
prefrontal cortex
Medizin und Gesundheit
open_access
Institut für Klinische Neurobiologie
Institut für Anatomie und Zellbiologie
Theodor-Boveri-Institut für Biowissenschaften
Lehrstuhl für Molekulare Psychiatrie
OpenAIRE
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/17031/026_Lesch_FRONTIERS-IN-CELLULAR-NEUROSCIENCE.pdf
21004
2020
eng
152
13
article
1
--
2020-08-11
--
Anxiety and Startle Phenotypes in Glrb Spastic and Glra1 Spasmodic Mouse Mutants
A GWAS study recently demonstrated single nucleotide polymorphisms (SNPs) in the human GLRB gene of individuals with a prevalence for agoraphobia. GLRB encodes the glycine receptor (GlyRs) β subunit. The identified SNPs are localized within the gene flanking regions (3′ and 5′ UTRs) and intronic regions. It was suggested that these nucleotide polymorphisms modify GlyRs expression and phenotypic behavior in humans contributing to an anxiety phenotype as a mild form of hyperekplexia. Hyperekplexia is a human neuromotor disorder with massive startle phenotypes due to mutations in genes encoding GlyRs subunits. GLRA1 mutations have been more commonly observed than GLRB mutations. If an anxiety phenotype contributes to the hyperekplexia disease pattern has not been investigated yet. Here, we compared two mouse models harboring either a mutation in the murine Glra1 or Glrb gene with regard to anxiety and startle phenotypes. Homozygous spasmodic animals carrying a Glra1 point mutation (alanine 52 to serine) displayed abnormally enhanced startle responses. Moreover, spasmodic mice exhibited significant changes in fear-related behaviors (freezing, rearing and time spent on back) analyzed during the startle paradigm, even in a neutral context. Spastic mice exhibit reduced expression levels of the full-length GlyRs β subunit due to aberrant splicing of the Glrb gene. Heterozygous animals appear normal without an obvious behavioral phenotype and thus might reflect the human situation analyzed in the GWAS study on agoraphobia and startle. In contrast to spasmodic mice, heterozygous spastic animals revealed no startle phenotype in a neutral as well as a conditioning context. Other mechanisms such as a modulatory function of the GlyRs β subunit within glycinergic circuits in neuronal networks important for fear and fear-related behavior may exist. Possibly, in human additional changes in fear and fear-related circuits either due to gene-gene interactions e.g., with GLRA1 genes or epigenetic factors are necessary to create the agoraphobia and in particular the startle phenotype.
Frontiers in Molecular Neuroscience
1662-5099
10.3389/fnmol.2020.00152
urn:nbn:de:bvb:20-opus-210041
Frontiers in Molecular Neuroscience 2020, 13:152. doi: 10.3389/fnmol.2020.00152
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Natascha Schaefer
Jérémy Signoret-Genest
Cora R. von Collenberg
Britta Wachter
Jürgen Deckert
Philip Tovote
Robert Blum
Carmen Villmann
eng
uncontrolled
glycine receptor
eng
uncontrolled
spastic
eng
uncontrolled
fear
eng
uncontrolled
anxiety
eng
uncontrolled
startle reaction
Medizin und Gesundheit
open_access
Institut für Klinische Neurobiologie
Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie
Import
Förderzeitraum 2020
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/21004/fnmol-13-00152.pdf
20198
2019
eng
bio042366
8
article
1
2020-03-17
--
--
An essential role of the mouse synapse-associated protein Syap1 in circuits for spontaneous motor activity and rotarod balance
Synapse-associated protein 1 (Syap1) is the mammalian homologue of synapse-associated protein of 47 kDa (Sap47) in Drosophila. Genetic deletion of Sap47 leads to deficiencies in short-term plasticity and associative memory processing in flies. In mice, Syap1 is prominently expressed in the nervous system, but its function is still unclear. We have generated Syap1 knockout mice and tested motor behaviour and memory. These mice are viable and fertile but display distinct deficiencies in motor behaviour. Locomotor activity specifically appears to be reduced in early phases when voluntary movement is initiated. On the rotarod, a more demanding motor test involving control by sensory feedback, Syap1-deficient mice dramatically fail to adapt to accelerated speed or to a change in rotation direction. Syap1 is highly expressed in cerebellar Purkinje cells and cerebellar nuclei. Thus, this distinct motor phenotype could be due to a so-far unknown function of Syap1 in cerebellar sensorimotor control. The observed motor defects are highly specific since other tests in the modified SHIRPA exam, as well as cognitive tasks like novel object recognition, Pavlovian fear conditioning, anxiety-like behaviour in open field dark-light transition and elevated plus maze do not appear to be affected in Syap1 knockout mice.
Biology Open
10.1242/bio.042366
urn:nbn:de:bvb:20-opus-201986
PDF includes: Correction: An essential role of the mouse synapse-associated protein Syap1 in circuits for spontaneous motor activity and rotarod balance - February 15, 2020. Biology Open (2020) 9, bio048942. doi:10.1242/bio.048942
Biology Open (2019) 8:042366. https://doi.org/10.1242/bio.042366
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Cora R. von Collenberg
Dominique Schmitt
Thomas Rülicke
Michael Sendtner
Robert Blum
Erich Buchner
eng
uncontrolled
Syap1 knockout
eng
uncontrolled
Motor behaviour
eng
uncontrolled
Associative learning
eng
uncontrolled
Fear conditioning
eng
uncontrolled
Object recognition
Biowissenschaften; Biologie
open_access
Institut für Klinische Neurobiologie
Förderzeitraum 2019
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/20198/vonCollenberg_theCompanyOfBiologists_2020.pdf
13030
2013
eng
e58259
3
8
article
1
2016-03-18
--
--
Ablation of BRaf Impairs Neuronal Differentiation in the Postnatal Hippocampus and Cerebellum
This study focuses on the role of the kinase BRaf in postnatal brain development. Mice expressing truncated, non-functional BRaf in neural stem cell-derived brain tissue demonstrate alterations in the cerebellum, with decreased sizes and fuzzy borders of the glomeruli in the granule cell layer. In addition we observed reduced numbers and misplaced ectopic Purkinje cells that showed an altered structure of their dendritic arborizations in the hippocampus, while the overall cornus ammonis architecture appeared to be unchanged. In male mice lacking BRaf in the hippocampus the size of the granule cell layer was normal at postnatal day 12 (P12) but diminished at P21, as compared to control littermates. This defect was caused by a reduced ability of dentate gyrus progenitor cells to differentiate into NeuN positive granule cell neurons. In vitro cell culture of P0/P1 hippocampal cells revealed that BRaf deficient cells were impaired in their ability to form microtubule-associated protein 2 positive neurons. Together with the alterations in behaviour, such as autoaggression and loss of balance fitness, these observations indicate that in the absence of BRaf all neuronal cellular structures develop, but neuronal circuits in the cerebellum and hippocampus are partially disturbed besides impaired neuronal generation in both structures.
PLoS ONE
10.1371/journal.pone.0058259
urn:nbn:de:bvb:20-opus-130304
PLoS ONE 8(3): e58259. doi:10.1371/journal.pone.0058259
Verena Pfeiffer
Rudolf Götz
Chaomei Xiang
Guadelupe Camarero
Attila Braun
Yina Zhang
Robert Blum
Helmut Heinsen
Bernhard Nieswandt
Ulf R. Rapp
eng
uncontrolled
granule cells
eng
uncontrolled
hippocampus
eng
uncontrolled
neurons
eng
uncontrolled
neuronal dendrites
eng
uncontrolled
embryos
eng
uncontrolled
dentate gyrus
eng
uncontrolled
neuronal differentiation
eng
uncontrolled
cerebellum
Medizin und Gesundheit
open_access
Institut für Klinische Neurobiologie
Institut für Medizinische Strahlenkunde und Zellforschung
Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie
Rudolf-Virchow-Zentrum
Institut für Experimentelle Biomedizin
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/13030/journal.pone.0058259.pdf