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Hammer C.,Max Planck Institute for Experimental Medicine | Wanitchakoo P.,University of Regensburg | Sirianant L.,University of Regensburg | Papiol S.,Max Planck Institute for Experimental Medicine | And 16 more authors.
Molecular Medicine | Year: 2015

In a first genome-wide association study (GWAS) approach to anti-Borrelia seropositivity, we identified two significant single nucleotide polymorphisms (SNPs) (rs17850869, P = 4.17E-09; rs41289586, P = 7.18E-08). Both markers, located on chromosomes 16 and 3, respectively, are within or close to genes previously connected to spinocerebellar ataxia. The risk SNP rs41289586 represents a missense variant (R263H) of anoctamin 10 (ANO10), a member of a protein family encoding Cl– channels and phospholipid scramblases. ANO10 augments volume-regulated Cl– currents (IHypo) in Xenopus oocytes, HEK293 cells, lymphocytes and macrophages and controls volume regulation by enhancing regulatory volume decrease (RVD). ANO10 supports migration of macrophages and phagocytosis of spirochetes. The R263H variant is inhibitory on IHypo, RVD and intracellular Ca2+ signals, which may delay spirochete clearance, thereby sensitizing adaptive immunity. Our data demonstrate for the first time that ANO10 has a central role in innate immune defense against Borrelia infection. © 2015 Molecular Medicine. All rights received.

Oku Y.,Hyogo College of Medicine | Fresemann J.,University of Gottingen | Miwakeichi F.,The Institute of Statistical Mathematics of Tokyo | Miwakeichi F.,Graduate University for Advanced Studies | And 2 more authors.
Respiratory Physiology and Neurobiology | Year: 2015

Astrocytes have been found to modulate neuronal activity through calcium-dependent signaling in various brain regions. However, whether astrocytes of the pre-Bötzinger complex (preBötC) exhibit respiratory rhythmic fluctuations is still controversial. Here we evaluated calcium-imaging experiments within preBötC in rhythmically active medullary slices from TgN(hGFAP-EGFP) mice using advanced analyses. 13.8% of EGFP-negative cells, putative neurons, showed rhythmic fluorescent changes that were highly correlated to the respiratory rhythmic fluctuation (cross-correlation coefficient. > 0.5 and d. F/. F . > 0.2%). In contrast, a considerable number of astrocyte somata exhibited synchronized low-frequency (<0.03. Hz) calcium oscillations. After band-pass filtering, signals that irregularly preceded the calcium signal of EGFP-negative cells were observed in 10.2% of astrocytes, indicating a functional coupling between astrocytes and neurons in preBötC. A model simulation confirmed that such preinspiratory astrocytic signals can arise from coupled neuronal and astrocytic oscillators, supporting a concept that slow oscillatory changes of astrocytic functions modulate neighboring neuronal activity to add variability in respiratory rhythm. © 2015 Elsevier B.V.

Borger M.,University of Gottingen | Funke S.,University of Mainz | Bahr M.,University of Gottingen | Bahr M.,Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain | And 3 more authors.
Basal Ganglia | Year: 2015

Parkinson's disease (PD) is the most frequent neurodegenerative movement disorder. In nearby future its importance will increase, especially due to changes in age structure. There are still substantial problems in terms of early diagnosis of the disease. In clinical practice, the diagnosis of PD is still based on the evaluation of clinical presentation and is supported by various ancillary tests with heterogeneous predictive value. In regard to diagnosis and disease monitoring, body fluid-based biomarkers have become an indispensable tool in today's medicine. In this Current Opinion we briefly address the present approaches to biomarker development for PD, including clinical trials on blood-based, cerebrospinal fluid-based and other body fluid-based biomarkers. We then review the knowledge on tear fluid-based biomarkers in general and discuss its usability as a source for biomarkers in PD patients. The close spatial relation of the lacrimal glands to the cranial nerves may predispose tear fluid to mirror pathophysiological changes in the central nervous system and argues for its validation as a biomarker in clinical studies. Based on the requirements for clinically useful biomarkers, we propose that tear fluid may serve as an easily accessible source for biomarkers in patients with PD and other neurodegenerative movement disorders. © 2015 Elsevier GmbH.

Woehler A.,Max Planck Institute for Biophysical Chemistry | Woehler A.,Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain | Lin K.-H.,Max Planck Institute for Biophysical Chemistry | Neher E.,Max Planck Institute for Biophysical Chemistry | Neher E.,Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain
Journal of Physiology | Year: 2014

Significantly more Ca2+ influx is required for eliciting release of neurotransmitter during whole cell patch clamp recording in the Calyx of Held, when gluconate with 3 mM free ATP is used as pipette filling solution, as compared to a methanesulfonate-based solution with excess Mg2+. This reduction in efficiency of Ca2+ in eliciting release is due to low-affinity Ca2+ binding of both gluconate and ATP2- anions. To study these effects we developed a simple fluorimeteric titration procedure, which reports the dissociation constant, KD, of a given Ca2+ indicator dye, multiplied by 1 plus the sum of Ca2+ binding ratios of any anions, which act as low-affinity Ca2+ ligands. For solutions without Ca2+ binding anions we find KD values for Fura2FF ranging from 11.5 ± 1.7 to 15.6 ± 7.47 μM depending on the dominant anion used. For Fura6F and KCl-based solutions we find KD = 17.8 ± 1.3 μM. For solutions with gluconate as the main anion and for solutions that contain nucleotides, such as ATP and GTP, we findmuch higher values for the product. Assuming that the KD of the indicator dye is equal to that of KCl-based solutions we calculate the summed Ca2+ binding ratios and find a value of 3.55 for a solution containing 100 mM potassium gluconate and 4 mM ATP. Gluconate contributes a value of 1.75 to this number, while the contribution of ATP depends strongly on the presence of Mg2+ and varies from 0.8 (with excess Mg2+) to 13.8 (in the presence of 3 mM free ATP). Methanesulfonate has negligible Ca2+ binding capacity. These results explain the reduced efficiency of Ca2+ influx in the presence of gluconate or nucleotides, as these anions are expected to intercept Ca2+ ions at short distance. © 2014 The Authors.

Papiol S.,Max Planck Institute for Experimental Medicine | Papiol S.,Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain | Mitjans M.,Max Planck Institute for Experimental Medicine | Mitjans M.,University of Barcelona | And 8 more authors.
Translational Psychiatry | Year: 2014

A recent publication reported an exciting polygenic effect of schizophrenia (SCZ) risk variants, identified by a large genome-wide association study (GWAS), on total brain and white matter volumes in schizophrenic patients and, even more prominently, in healthy subjects. The aim of the present work was to replicate and then potentially extend these findings. According to the original publication, polygenic risk scores - using single nucleotide polymorphism (SNP) information of SCZ GWAS - (polygenic SCZ risk scores; PSS) were calculated in 122 healthy subjects, enrolled in a structural magnetic resonance imaging (MRI) study. These scores were computed based on P-values and odds ratios available through the Psychiatric GWAS Consortium. In addition, polygenic white matter scores (PWM) were calculated, using the respective SNP subset in the original publication. None of the polygenic scores, either PSS or PWM, were found to be associated with total brain, white matter or gray matter volume in our replicate sample. Minor differences between the original and the present study that might have contributed to lack of reproducibility (but unlikely explain it fully), are number of subjects, ethnicity, age distribution, array technology, SNP imputation quality and MRI scanner type. In contrast to the original publication, our results do not reveal the slightest signal of association of the described sets of GWAS-identified SCZ risk variants with brain volumes in adults. Caution is indicated in interpreting studies building on polygenic risk scores without replication sample. © 2014 Macmillan Publishers Limited All rights reserved.

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