@article{KlitschEvdokimovFranketal.2020, author = {Klitsch, Alexander and Evdokimov, Dimitar and Frank, Johanna and Thomas, Dominique and Saffer, Nadine and Meyer zu Altenschildesche, Caren and Sisignano, Marco and Kampik, Daniel and Malik, Rayaz A. and Sommer, Claudia and {\"U}{\c{c}}eyler, Nurcan}, title = {Reduced association between dendritic cells and corneal sub-basal nerve fibers in patients with fibromyalgia syndrome}, series = {Journal of the Peripheral Nervous System}, volume = {25}, journal = {Journal of the Peripheral Nervous System}, number = {1}, doi = {10.1111/jns.12360}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-214150}, pages = {9-18}, year = {2020}, abstract = {In our study, we aimed at investigating corneal langerhans cells (LC) in patients with fibromyalgia syndrome (FMS) and small fiber neuropathy (SFN) as potential contributors to corneal small fiber pathology. We enrolled women with FMS (n = 134) and SFN (n = 41) who underwent neurological examination, neurophysiology, prostaglandin analysis in tear fluid, and corneal confocal microscopy (CCM). Data were compared with those of 60 age-matched female controls. After screening for dry eye disease, corneal LC were counted and sub-classified as dendritic (dLC) and non-dendritic (ndLC) cells with or without nerve fiber association. We further analyzed corneal nerve fiber density (CNFD), length (CNFL), and branch density (CNBD). Neurological examination indicated deficits of small fiber function in patients with SFN. Nerve conduction studies were normal in all participants. Dry eye disease was more prevalent in FMS (17\%) and SFN (28\%) patients than in controls (5\%). Tear fluid prostaglandin levels did not differ between FMS patients and controls. While corneal LC density in FMS and SFN patients was not different from controls, there were fewer dLC in association with nerve fibers in FMS and SFN patients than in controls (P < .01 each). Compared to controls, CNFL was lower in FMS and SFN patients (P < .05 each), CNFD was lower only in FMS patients (P < .05), and CNBD was lower only in SFN patients (P < .001). There was no difference in any CCM parameter between patients with and without dry eyes. Our data indicate changes in corneal innervation and LC distribution in FMS and SFN, potentially based on altered LC signaling.}, language = {en} } @article{WirschingOrtUeceyler2020, author = {Wirsching, Isabelle and Ort, Nora and {\"U}{\c{c}}eyler, Nurcan}, title = {ALS or ALS mimic by neuroborreliosis — A case report}, series = {Clinical Case Reports}, volume = {8}, journal = {Clinical Case Reports}, doi = {10.1002/ccr3.2569}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201308}, pages = {86-91}, year = {2020}, abstract = {Comprehensive investigation in motor neuron disease is vital not to miss a treatable differential diagnosis. Neuroborreliosis should be considered during an ALS work-up. However, false-positive CSF results do occur, and thus, results should be interpreted carefully in context of all clinical test results.}, language = {en} } @phdthesis{Frank2019, author = {Frank, Johanna}, title = {Untersuchung der Kleinfaserpathologie beim Fibromyalgie-Syndrom}, publisher = {Annals of Neurology, The Journal of Rheumatology}, doi = {10.25972/OPUS-19265}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-192653}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2019}, abstract = {Die Studienergebnisse st{\"u}tzen das Konzept, dass das periphere Nervensystem zu Schmerzen beim Fibromyalgie-Syndrom (FMS) beitr{\"a}gt. An der Neurologischen Universit{\"a}tsklinik W{\"u}rzburg wurden 53 FMS Patientinnen und 35 gesunde Kontrollen rekrutiert, ausf{\"u}hrlich anamnestiziert inklusive spezieller Schmerzfrageb{\"o}gen, neurologisch und mittels spezieller Tests auf eine St{\"o}rung der kleinkalibrigen A-delta- und C-Nervenfasern untersucht. Hierzu geh{\"o}rte eine quantitative sensorische Testung mit Pleasant touch Untersuchung und die schmerz-assoziierten elektrisch-evoziierten Potentiale f{\"u}r die Kleinfaserfunktion und die corneale confocale Mikroskopie, sowie die Analyse von Hautstanbiopsien f{\"u}r die Kleinfasermorphologie. Im Unterschied zu gesunden Kontrollen wiesen die FMS Patientinnen eine Reduktion, als auch eine Funktions{\"a}nderung der kleinkalibrigen Nervenfasern auf. Des Weiteren konnten wir aus der heterogenen Patientenpopulation anhand von unterschiedlichen Nervenfaserdichten der Haut eine Subgruppe mit generalisierter Reduktion der Hautinnervation identifizieren, die besonders schwer betroffen ist. Diese Subgruppenanalysen k{\"o}nnen k{\"u}nftig von großer Bedeutung f{\"u}r die Therapiewahl sein.}, subject = {Fibromyalgie}, language = {de} } @phdthesis{Kuzkina2020, author = {Kuzkina, Anastasia}, title = {Dermal α-synuclein oligomers and aggregates in Parkinson's disease}, doi = {10.25972/OPUS-20436}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-204369}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Lewy bodies and Lewy neurites are neuropathological hallmarks of Parkinson's disease (PD). These depositions in the brain mostly consist of aggregated α-synuclein (α-syn) phosphorylated at Ser129. A number of studies reported detection of phosphorylated α-syn (p-α-syn) in the dermal nerve fibers in Parkinson's disease. The objective of this study was to investigate whether pathological α-syn accumulations detected in the skin represent aggregated protein. A number of methods aimed at detecting α-syn oligomers and aggregates were first tested and optimized on the brain samples in PD and normal control. These methods included proximity ligation assay (PLA), PET-blot, immunohistochemical (IHC) stains with α-syn aggregate (5G4) or oligomer specific (ASyO5) antibodies and a stain against native α-syn (syn211) after proteinase K (PK) digestion. Subsequently, the most specific methods (stains with 5G4, ASyO5 and syn211 after PK digestion) were studied in two separate patient and control cohorts. Anti-p-α-syn stain was performed in parallel. Single sections from at least 2 biopsy sites from 44 patients and 22 controls (cohort 1) as well as serial sections of 4 biopsy sites from 27 patients and 5 controls (cohort 2) were systematically studied for presence of aggregated and oligomeric α-syn. In total, 5G4 positive deposits were found in 24\% (cohort 1) and 37\% (cohort 2), ASyO5 positive lesions in 17,7\% (cohort 1) and 33\% (cohort 2), syn211 positive lesions after PK digestion in 38,7\% (cohort 1) and 48\% (cohort 2) of cases. There was a major overlap among positivity for a particular staining on the patient level and in most cases, the same nerve fiber was found to be positive for all 4 markers in neighboring sections. Among the skin biopsies which contained p-α-syn accumulation, 59\% were also PK resistant, 41\% were 5G4 positive and 45\% were ASyO5 positive. The samples belonging to normal controls did not show any positive signal in either of the newly established stainings or in the anti-p-α-syn staining. Using 3 distinct IHC methods, α-syn oligomers and aggregates were detectable in the majority of p-α-syn positive skin biopsies. This finding supports the hypothesis that α-syn aggregation occurs in the peripheral (i.e. dermal) nerves and can be specifically detected using skin biopsy.}, subject = {Parkinson-Krankheit}, language = {en} } @phdthesis{Toeppner2020, author = {T{\"o}ppner, Verena}, title = {Therapie und Outcome von Patienten mit aneurysmatischer Subarachnoidalblutung am Universit{\"a}tsklinikum W{\"u}rzburg}, doi = {10.25972/OPUS-20912}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-209129}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Die aneurysmatische SAB ist trotz etablierter Therapieverfahren (Coiling und Clipping) weiterhin ein Krankheitsbild mit hoher Mortalit{\"a}t. In unserer Arbeit haben wir retrospektiv die Patientenakten der Patienten, die mit der Diagnose aneurysmatische SAB am Universit{\"a}tsklinikum W{\"u}rzburg zwischen dem 01.01.1999 und dem 31.12.2009 aufgenommen wurden, ausgewertet. Es konnte dargestellt werden das als Hauptrisikofaktoren f{\"u}r ein schlechtes Therapieergebnis ein schlechter Aufnahmestatus des Patienten und das Auftreten von Komplikationen im Verlauf verantwortlich sind.}, subject = {Subarachnoidalblutung}, language = {de} } @phdthesis{Buchwald2020, author = {Buchwald, Sina}, title = {Autoimmune Enzephalitiden am Universit{\"a}tsklinikum W{\"u}rzburg von 2006-2016}, doi = {10.25972/OPUS-20720}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-207202}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {In den Jahren von 2006 bis 2016 sind am Universit{\"a}tsklinikum W{\"u}rzburg insgesamt 26 Patienten mit der Diagnose einer Autoimmunen Enzephalitis behandelt worden. Diese Arbeit zeigt ihre Krankheitsverl{\"a}ufe, Outcome, die gefundenen Antik{\"o}rper und die Therapien der jeweiligen Patienten. Im zweiten Schritt wurden die Daten mit den in der Literatur bereits beschrieben F{\"a}llen verglichen, um Gemeinsamkeiten, aber auch Unterschiede aufzeigen zu k{\"o}nnen.}, subject = {Enzephalitis}, language = {de} } @article{SilwedelSpeerHaarmannetal.2018, author = {Silwedel, Christine and Speer, Christian P. and Haarmann, Axel and Fehrholz, Markus and Claus, Heike and Buttmann, Mathias and Glaser, Kirsten}, title = {Novel insights into neuroinflammation: bacterial lipopolysaccharide, tumor necrosis factor α, and Ureaplasma species differentially modulate atypical chemokine receptor 3 responses in human brain microvascular endothelial cells}, series = {Journal of Neuroinflammation}, volume = {15}, journal = {Journal of Neuroinflammation}, number = {156}, doi = {10.1186/s12974-018-1170-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-175952}, year = {2018}, abstract = {Background: Atypical chemokine receptor 3 (ACKR3, synonym CXCR7) is increasingly considered relevant in neuroinflammatory conditions, in which its upregulation contributes to compromised endothelial barrier function and may ultimately allow inflammatory brain injury. While an impact of ACKR3 has been recognized in several neurological autoimmune diseases, neuroinflammation may also result from infectious agents, including Ureaplasma species (spp.). Although commonly regarded as commensals of the adult urogenital tract, Ureaplasma spp. may cause invasive infections in immunocompromised adults as well as in neonates and appear to be relevant pathogens in neonatal meningitis. Nonetheless, clinical and in vitro data on Ureaplasma-induced inflammation are scarce. Methods: We established a cell culture model of Ureaplasma meningitis, aiming to analyze ACKR3 variances as a possible pathomechanism in Ureaplasma-associated neuroinflammation. Non-immortalized human brain microvascular endothelial cells (HBMEC) were exposed to bacterial lipopolysaccharide (LPS) or tumor necrosis factor-α (TNF-α), and native as well as LPS-primed HBMEC were cultured with Ureaplasma urealyticum serovar 8 (Uu8) and U. parvum serovar 3 (Up3). ACKR3 responses were assessed via qRT-PCR, RNA sequencing, flow cytometry, and immunocytochemistry. Results: LPS, TNF-α, and Ureaplasma spp. influenced ACKR3 expression in HBMEC. LPS and TNF-α significantly induced ACKR3 mRNA expression (p < 0.001, vs. control), whereas Ureaplasma spp. enhanced ACKR3 protein expression in HBMEC (p < 0.01, vs. broth control). Co-stimulation with LPS and either Ureaplasma isolate intensified ACKR3 responses (p < 0.05, vs. LPS). Furthermore, stimulation wielded a differential influence on the receptor's ligands. Conclusions: We introduce an in vitro model of Ureaplasma meningitis. We are able to demonstrate a pro-inflammatory capacity of Ureaplasma spp. in native and, even more so, in LPS-primed HBMEC, underlining their clinical relevance particularly in a setting of co-infection. Furthermore, our data may indicate a novel role for ACKR3, with an impact not limited to auto-inflammatory diseases, but extending to infection-related neuroinflammation as well. AKCR3-induced blood-brain barrier breakdown might constitute a potential common pathomechanism.}, language = {en} } @article{HofmannKarlSommeretal.2017, author = {Hofmann, Lukas and Karl, Franziska and Sommer, Claudia and {\"U}{\c{c}}eyler, Nurcan}, title = {Affective and cognitive behavior in the alpha-galactosidase A deficient mouse model of Fabry disease}, series = {PLoS ONE}, volume = {12}, journal = {PLoS ONE}, number = {6}, doi = {10.1371/journal.pone.0180601}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170745}, pages = {e0180601}, year = {2017}, abstract = {Fabry disease is an X-linked inherited lysosomal storage disorder with intracellular accumulation of globotriaosylceramide (Gb3) due to α-galactosidase A (α-Gal A) deficiency. Fabry patients frequently report of anxiety, depression, and impaired cognitive function. We characterized affective and cognitive phenotype of male mice with α-Gal A deficiency (Fabry KO) and compared results with those of age-matched male wildtype (WT) littermates. Young (3 months) and old (≥ 18 months) mice were tested in the na{\"i}ve state and after i.pl. injection of complete Freund`s adjuvant (CFA) as an inflammatory pain model. We used the elevated plus maze (EPM), the light-dark box (LDB) and the open field test (OF) to investigate anxiety-like behavior. The forced swim test (FST) and Morris water maze (MWM) were applied to assess depressive-like and learning behavior. The EPM test revealed no intergroup difference for anxiety-like behavior in na{\"i}ve young and old Fabry KO mice compared to WT littermates, except for longer time spent in open arms of the EPM for young WT mice compared to young Fabry KO mice (p<0.05). After CFA injection, young Fabry KO mice showed increased anxiety-like behavior compared to young WT littermates (p<0.05) and na{\"i}ve young Fabry KO mice (p<0.05) in the EPM as reflected by shorter time spent in EPM open arms. There were no relevant differences in the LDB and the OF test, except for longer time spent in the center zone of the OF by young WT mice compared to young Fabry KO mice (p<0.05). Complementary to this, depression-like and learning behavior were not different between genotypes and age-groups, except for the expectedly lower memory performance in older age-groups compared to young mice. Our results indicate that genetic influences on affective and cognitive symptoms in FD may be of subordinate relevance, drawing attention to potential influences of environmental and epigenetic factors.}, language = {en} } @article{PiroEckesKasaragodetal.2021, author = {Piro, Inken and Eckes, Anna-Lena and Kasaragod, Vikram Babu and Sommer, Claudia and Harvey, Robert J. and Schaefer, Natascha and Villmann, Carmen}, title = {Novel Functional Properties of Missense Mutations in the Glycine Receptor β Subunit in Startle Disease}, series = {Frontiers in Molecular Neuroscience}, volume = {14}, journal = {Frontiers in Molecular Neuroscience}, issn = {1662-5099}, doi = {10.3389/fnmol.2021.745275}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-246676}, year = {2021}, abstract = {Startle disease is a rare disorder associated with mutations in GLRA1 and GLRB, encoding glycine receptor (GlyR) α1 and β subunits, which enable fast synaptic inhibitory transmission in the spinal cord and brainstem. The GlyR β subunit is important for synaptic localization via interactions with gephyrin and contributes to agonist binding and ion channel conductance. Here, we have studied three GLRB missense mutations, Y252S, S321F, and A455P, identified in startle disease patients. For Y252S in M1 a disrupted stacking interaction with surrounding aromatic residues in M3 and M4 is suggested which is accompanied by an increased EC\(_{50}\) value. By contrast, S321F in M3 might stabilize stacking interactions with aromatic residues in M1 and M4. No significant differences in glycine potency or efficacy were observed for S321F. The A455P variant was not predicted to impact on subunit folding but surprisingly displayed increased maximal currents which were not accompanied by enhanced surface expression, suggesting that A455P is a gain-of-function mutation. All three GlyR β variants are trafficked effectively with the α1 subunit through intracellular compartments and inserted into the cellular membrane. In vivo, the GlyR β subunit is transported together with α1 and the scaffolding protein gephyrin to synaptic sites. The interaction of these proteins was studied using eGFP-gephyrin, forming cytosolic aggregates in non-neuronal cells. eGFP-gephyrin and β subunit co-expression resulted in the recruitment of both wild-type and mutant GlyR β subunits to gephyrin aggregates. However, a significantly lower number of GlyR β aggregates was observed for Y252S, while for mutants S321F and A455P, the area and the perimeter of GlyR β subunit aggregates was increased in comparison to wild-type β. Transfection of hippocampal neurons confirmed differences in GlyR-gephyrin clustering with Y252S and A455P, leading to a significant reduction in GlyR β-positive synapses. Although none of the mutations studied is directly located within the gephyrin-binding motif in the GlyR β M3-M4 loop, we suggest that structural changes within the GlyR β subunit result in differences in GlyR β-gephyrin interactions. Hence, we conclude that loss- or gain-of-function, or alterations in synaptic GlyR clustering may underlie disease pathology in startle disease patients carrying GLRB mutations.}, language = {en} } @article{WagenhaeuserRickertSommeretal.2022, author = {Wagenh{\"a}user, Laura and Rickert, Vanessa and Sommer, Claudia and Wanner, Christoph and Nordbeck, Peter and Rost, Simone and {\"U}{\c{c}}eyler, Nurcan}, title = {X-chromosomal inactivation patterns in women with Fabry disease}, series = {Molecular Genetics \& Genomic Medicine}, volume = {10}, journal = {Molecular Genetics \& Genomic Medicine}, number = {9}, doi = {10.1002/mgg3.2029}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312795}, year = {2022}, abstract = {Background Although Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene (GLA), women may develop severe symptoms. We investigated X-chromosomal inactivation patterns (XCI) as a potential determinant of symptom severity in FD women. Patients and Methods We included 95 women with mutations in GLA (n = 18 with variants of unknown pathogenicity) and 50 related men, and collected mouth epithelial cells, venous blood, and skin fibroblasts for XCI analysis using the methylation status of the androgen receptor gene. The mutated X-chromosome was identified by comparison of samples from relatives. Patients underwent genotype categorization and deep clinical phenotyping of symptom severity. Results 43/95 (45\%) women carried mutations categorized as classic. The XCI pattern was skewed (i.e., ≥75:25\% distribution) in 6/87 (7\%) mouth epithelial cell samples, 31/88 (35\%) blood samples, and 9/27 (33\%) skin fibroblast samples. Clinical phenotype, α-galactosidase A (GAL) activity, and lyso-Gb3 levels did not show intergroup differences when stratified for X-chromosomal skewing and activity status of the mutated X-chromosome. Conclusions X-inactivation patterns alone do not reliably reflect the clinical phenotype of women with FD when investigated in biomaterial not directly affected by FD. However, while XCI patterns may vary between tissues, blood frequently shows skewing of XCI patterns.}, language = {en} }