Tolö, Nils Johan

[["dc.bibliographiccitation.firstpage","109"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Annals of Neurology"],["dc.bibliographiccitation.lastpage","118"],["dc.bibliographiccitation.volume","74"],["dc.contributor.author","Taschenberger, G."],["dc.contributor.author","Toloe, J."],["dc.contributor.author","Tereshchenko, J."],["dc.contributor.author","Akerboom, J."],["dc.contributor.author","Wales, P."],["dc.contributor.author","Benz, R."],["dc.contributor.author","Becker, Stefan"],["dc.contributor.author","Outeiro, T. F."],["dc.contributor.author","Looger, L. L."],["dc.contributor.author","Bähr, M."],["dc.contributor.author","Zweckstetter, M."],["dc.contributor.author","Kügler, Sebastian"],["dc.date.accessioned","2017-09-07T11:47:39Z"],["dc.date.available","2017-09-07T11:47:39Z"],["dc.date.issued","2013"],["dc.description.abstract","ObjectiveWhereas the contribution of -synuclein to neurodegeneration in Parkinson disease is well accepted, the putative impact of its close homologue, -synuclein, is enigmatic. -Synuclein is widely expressed throughout the central nervous system, as is -synuclein, but the physiological functions of both proteins remain unknown. Recent findings have supported the view that -synuclein can act as an ameliorating regulator of -synuclein-induced neurotoxicity, having neuroprotective rather than neurodegenerative capabilities, and being nonaggregating due to the absence of most of the aggregation-promoting NAC domain. However, a mutation of -synuclein linked to dementia with Lewy bodies rendered the protein neurotoxic in transgenic mice, and fibrillation of -synuclein has been demonstrated in vitro. MethodsNeurotoxicity and aggregation properties of -, -, and -synuclein were comparatively elucidated in the rat nigro-striatal projection and in cultured neurons. ResultsSupporting the hypothesis that -synuclein can act as a neurodegeneration-inducing factor, we demonstrated that wild-type -synuclein is neurotoxic for cultured primary neurons. Furthermore, -synuclein formed proteinase K-resistant aggregates in dopaminergic neurons in vivo, leading to pronounced and progressive neurodegeneration in rats. Expression of -synuclein caused mitochondrial fragmentation, but this fragmentation did not render mitochondria nonfunctional in terms of ion handling and respiration even at late stages of neurodegeneration. A comparison of the neurodegenerative effects induced by -, -, and -synuclein revealed that -synuclein was eventually as neurotoxic as -synuclein for nigral dopaminergic neurons, whereas -synuclein proved to be nontoxic and had very low aggregation propensity. InterpretationOur results suggest that the role of -synuclein as a putative modulator of neuropathology in aggregopathies like Parkinson disease and dementia with Lewy bodies needs to be revisited. Ann Neurol 2013;74:109-118"],["dc.identifier.doi","10.1002/ana.23905"],["dc.identifier.gro","3142329"],["dc.identifier.isi","000329198600014"],["dc.identifier.pmid","23536356"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/7075"],["dc.language.iso","en"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.eissn","1531-8249"],["dc.relation.issn","0364-5134"],["dc.title","β-Synuclein Aggregates and Induces Neurodegeneration in Dopaminergic Neurons"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","47"],["dc.bibliographiccitation.journal","Molecular and Cellular Neuroscience"],["dc.bibliographiccitation.lastpage","56"],["dc.bibliographiccitation.volume","59"],["dc.contributor.author","Toloe, J."],["dc.contributor.author","Mollajew, R."],["dc.contributor.author","Kuegler, Sebastian"],["dc.contributor.author","Mironov, Sergej L."],["dc.date.accessioned","2018-11-07T09:42:51Z"],["dc.date.available","2018-11-07T09:42:51Z"],["dc.date.issued","2014"],["dc.description.abstract","Understanding metabolic control of neuronal function requires detailed knowledge of ATP handling in living neurons. We imaged ATP in organotypic hippocampal slices using genetically encoded sensor Ateam 1.03 modified to selectively transduce neurons in the tissue. ATP imaging indicated distinct differences in ATP production and consumption in dentate gyrus and cornu ammonis (CA) areas. Removal of extracellular Mg2+ from the bath evoked epileptiform-like activity that was accompanied by ATP decline from 2-3 to 1-2 mM. The slices fully recovered from treatment and showed persistent spontaneous activity. Neuronal discharges were followed by transient ATP changes and periodic activation of ATP-sensitive K+ (K-ATP) channels. The biggest ATP decreases during epileptiform-like episodes of activity were observed in CA1 and CA3 neurons. Examination of neurons from the Rett model mice MeCP2(-/y) showed that seizure-like activity had earlier onset and subsequent spontaneous activity demonstrated more frequent discharges. Hippocampal MeCP2(-/y) neurons had higher resting ATP levels and showed bigger ATP decreases during epileptiform-like activity. More intense ATP turnover in MeCP2(-/y) neurons may result from necessity to maintain hippocampal function in Rett syndrome. Elevated ATP may make, in turn, Rett hippocampus more prone to epilepsy due to inadequate activity of K-ATP channels. (C) 2014 Elsevier Inc. All rights reserved."],["dc.identifier.doi","10.1016/j.mcn.2013.12.008"],["dc.identifier.isi","000336338400005"],["dc.identifier.pmid","24394521"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/34052"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Academic Press Inc Elsevier Science"],["dc.relation.issn","1095-9327"],["dc.relation.issn","1044-7431"],["dc.title","Metabolic differences in hippocampal 'Ratt' neurons revealed by ATP imaging"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","142"],["dc.bibliographiccitation.journal","Frontiers in Molecular Neuroscience"],["dc.bibliographiccitation.volume","10"],["dc.contributor.author","Zahur, Muzna"],["dc.contributor.author","Tolö, Johan"],["dc.contributor.author","Bähr, Mathias"],["dc.contributor.author","Kügler, Sebastian"],["dc.date.accessioned","2018-04-23T11:46:58Z"],["dc.date.available","2018-04-23T11:46:58Z"],["dc.date.issued","2017"],["dc.description.abstract","Gene editing tools like TALENs, ZFNs and Crispr/Cas now offer unprecedented opportunities for targeted genetic manipulations in virtually all species. Most of the recent research in this area has concentrated on manipulation of the genome in isolated cells, which then give rise to transgenic animals or modified stem cell lines. Much less is known about applicability of genetic scissors in terminally differentiated, non-dividing cells like neurons of the adult brain. We addressed this question by expression of a pair of ZFNs targeting the murine cathepsin D gene in CNS neurons by means of an optimized AAV viral vector. We show that ZFN expression resulted in substantial depletion of cathepsin D from neuronal lysosomes, demonstrating a robust gene deletion. Importantly, long-term ZFN expression in CNS neurons did not impair essential neuronal functionality and did not cause inflammation or neurodegeneration, suggesting that potent genetic scissors can be expressed safely in the mouse brain. This finding opens up new venues to create novel research models for neurodegenerative disorders."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2017"],["dc.identifier.doi","10.3389/fnmol.2017.00142"],["dc.identifier.gro","3142072"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/14497"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/13278"],["dc.language.iso","en"],["dc.notes.intern","lifescience updates Crossref Import"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","final"],["dc.relation.issn","1662-5099"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Long-Term Assessment of AAV-Mediated Zinc Finger Nuclease Expression in the Mouse Brain"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.peerReviewed","no"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","49"],["dc.bibliographiccitation.journal","Frontiers in Molecular Neuroscience"],["dc.bibliographiccitation.volume","11"],["dc.contributor.author","Tolö, Johan"],["dc.contributor.author","Taschenberger, Grit"],["dc.contributor.author","Leite, Kristian"],["dc.contributor.author","Stahlberg, Markus A."],["dc.contributor.author","Spehlbrink, Gesche"],["dc.contributor.author","Kues, Janina"],["dc.contributor.author","Munari, Francesca"],["dc.contributor.author","Capaldi, Stefano"],["dc.contributor.author","Becker, Stefan"],["dc.contributor.author","Zweckstetter, Markus"],["dc.contributor.author","Dean, Camin"],["dc.contributor.author","Bähr, Mathias"],["dc.contributor.author","Kügler, Sebastian"],["dc.date.accessioned","2019-07-09T11:45:10Z"],["dc.date.available","2019-07-09T11:45:10Z"],["dc.date.issued","2018"],["dc.description.abstract","α-Synuclein (α-Syn) is intimately linked to the etiology of Parkinson's Disease, as mutations and even subtle increases in gene dosage result in early onset of the disease. However, how this protein causes neuronal dysfunction and neurodegeneration is incompletely understood. We thus examined a comprehensive range of physiological parameters in cultured rat primary neurons overexpressing α-Syn at levels causing a slowly progressive neurodegeneration. In contradiction to earlier reports from non-neuronal assay systems we demonstrate that α-Syn does not interfere with essential ion handling capacities, mitochondrial capability of ATP production or basic electro-physiological properties like resting membrane potential or the general ability to generate action potentials. α-Syn also does not activate canonical stress kinase Signaling converging on SAPK/Jun, p38 MAPK or Erk kinases. Causative for α-Syn-induced neurodegeneration are mitochondrial thiol oxidation and activation of caspases downstream of mitochondrial outer membrane permeabilization, leading to apoptosis-like cell death execution with some unusual aspects. We also aimed to elucidate neuroprotective strategies counteracting the pathophysiological processes caused by α-Syn. Neurotrophic factors, calpain inhibition and increased lysosomal protease capacity showed no protective effects against α-Syn overexpression. In contrast, the major watchdog of outer mitochondrial membrane integrity, Bcl-Xl, was capable of almost completely preventing neuron death, but did not prevent mitochondrial thiol oxidation. Importantly, independent from the quite mono-causal induction of neurotoxicity, α-Syn causes diminished excitability of neurons by external stimuli and robust impairments in endogenous neuronal network activity by decreasing the frequency of action potentials generated without external stimulation. This latter finding suggests that α-Syn can induce neuronal dysfunction independent from its induction of neurotoxicity and might serve as an explanation for functional deficits that precede neuronal cell loss in synucleopathies like Parkinson's disease or dementia with Lewy bodies."],["dc.identifier.doi","10.3389/fnmol.2018.00049"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15047"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59171"],["dc.language.iso","en"],["dc.notes.intern","DeepGreen Import"],["dc.publisher","Frontiers Media S.A."],["dc.relation.eissn","1662-5099"],["dc.relation.issn","1662-5099"],["dc.rights","http://creativecommons.org/licenses/by/4.0/"],["dc.subject.ddc","610"],["dc.title","Pathophysiological Consequences of Neuronal α-Synuclein Overexpression: Impacts on Ion Homeostasis, Stress Signaling, Mitochondrial Integrity, and Electrical Activity"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","2593"],["dc.bibliographiccitation.issue","10"],["dc.bibliographiccitation.journal","The Journal of Physiology"],["dc.bibliographiccitation.lastpage","2609"],["dc.bibliographiccitation.volume","591"],["dc.contributor.author","Mollajew, R."],["dc.contributor.author","Toloe, J."],["dc.contributor.author","Mironov, Sergej L."],["dc.date.accessioned","2018-11-07T09:25:07Z"],["dc.date.available","2018-11-07T09:25:07Z"],["dc.date.issued","2013"],["dc.description.abstract","Key points center dot KATP channels can suppress overexcitation of CNS neurons after activation of glutamatergic receptors (GluRs), and we examined this functional interaction in the brainstem and hippocampal neurons. center dot GluR stimulation increased the activity of single KATP channels that was not mediated by intracellular calcium, reactive oxygen species and osmotic stress, and was abolished after inhibition of sodium influx. center dot ATP and sodium imaging indicated that functional cross-talk between GluRs and KATP channels is mediated by Na+-K+-ATPase. center dot GluR contributed to KATP channel opening during hypoxia in functionally intact brainstem slices and seizure-like activity in the hippocampal slices. center dot We propose that neuronal activity depletes submembrane ATP, and increases ADP levels and promotes KATP channel opening that dampen uncontrolled excitation by glutamate. Abstract Excessive stimulation of glutamatergic receptors (GluRs) can overexcite neurons. This can be dampened by KATP channels linking metabolic and neuronal activities, but the cross-talk has not yet been examined on the single channel level. In the brainstem and hippocampal neurons, GluR agonists augmented the open state probability (Popen) of KATP channels with relative efficacy: kainate approximate to AMPA > NMDA > t-ACPD. Inhibition of calcium influx and chelation of intracellular calcium did not modify the effects. Kainate did not augment production of reactive oxygen species measured with roGFP1. H2O2 slightly increased Popen, but GluR effects were not modified. GluR actions were abolished in Na+-free solutions and after blockade of Na+-K+-ATPase. KATP channels in open-cell patch-clamp measurements were inhibited by ATP, stimulated by ADP, and kainate was effective only in the presence of ATP. GluR stimulation enhanced ATP consumption that decreased submembrane ATP levels, whereas metabolic poisoning diminished bulk ATP. Modelling showed strong ATP depletion and ADP accumulation near the membrane, and both effects contributed to Popen increases after GluR stimulation. Kainate and hypoxia activated KATP channels in the functional brainstem slices. Inhibition of aerobic ATP production and GluR stimulation were about equally effective in KATP channel opening during hypoxia. Induction of seizure-like activity in hippocampal slices with Mg2+-free solutions was accompanied by ATP decrease and KATP channel opening. We propose that KATP channels and GluRs are functionally coupled that can regulate long-lasting changes of neuronal activity in the CNS neurons."],["dc.identifier.doi","10.1113/jphysiol.2012.248369"],["dc.identifier.isi","000319016200019"],["dc.identifier.pmid","23507878"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/29992"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Wiley-blackwell"],["dc.relation.issn","0022-3751"],["dc.title","Single KATP channel opening in response to stimulation of AMPA/kainate receptors is mediated by Na+ accumulation and submembrane ATP and ADP changes"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","UNSP 2"],["dc.bibliographiccitation.journal","Frontiers in Molecular Neuroscience"],["dc.bibliographiccitation.volume","6"],["dc.contributor.author","Akerboom, Jasper"],["dc.contributor.author","Calderon, Nicole Carreras"],["dc.contributor.author","Tian, Lin"],["dc.contributor.author","Wabnig, Sebastian"],["dc.contributor.author","Prigge, Matthias"],["dc.contributor.author","Tolo, Johan"],["dc.contributor.author","Gordus, Andrew"],["dc.contributor.author","Orger, Michael B."],["dc.contributor.author","Severi, Kristen E."],["dc.contributor.author","Macklin, John J."],["dc.contributor.author","Patel, Ronak"],["dc.contributor.author","Pulver, Stefan R."],["dc.contributor.author","Wardill, Trevor J."],["dc.contributor.author","Fischer, Elisabeth"],["dc.contributor.author","Schueler, Christina"],["dc.contributor.author","Chen, Tsai-Wen"],["dc.contributor.author","Sarkisyan, Karen S."],["dc.contributor.author","Marvin, Jonathan S."],["dc.contributor.author","Bargmann, Cornelia I."],["dc.contributor.author","Kim, Douglas S."],["dc.contributor.author","Kugler, Sebastian"],["dc.contributor.author","Lagnado, Leon"],["dc.contributor.author","Hegemann, Peter"],["dc.contributor.author","Gottschalk, Alexander"],["dc.contributor.author","Schreiter, Eric R."],["dc.contributor.author","Looger, Loren L."],["dc.date.accessioned","2018-11-07T09:30:57Z"],["dc.date.available","2018-11-07T09:30:57Z"],["dc.date.issued","2013"],["dc.description.abstract","Genetically encoded calcium indicators (GECIs) are powerful tools for systems neuroscience. Here we describe red, single wavelength GECIs, \"RCaMPs,\" engineered from circular permutation of the thermostable red fluorescent protein mRuby. High-resolution crystal structures of mRuby, the red sensor RCaMP and the recently published red GECI R-GECO1 give insight into the chromophore environments of the Ca2+-bound state of the sensors and the engineered protein domain interfaces of the different indicators. We characterized the biophysical properties and performance of RCaMP sensors in vitro and in vivo in Caenorhabditis elegans, Drosophila larvae, and larval zebrafish. Further, we demonstrate 2-color calcium imaging both within the same cell (registering rnitochondrial and somatic [Ca2+]) and between two populations of cells: neurons and astrocytes. Finally, we perform integrated optogenetics experiments, wherein neural activation via channelrhodopsin-2 (ChR2) or a red-shifted variant, and activity imaging via RCaMP or GCaMe are conducted simultaneously, with the ChR2/RCaMP pair providing independently addressable spectral channels. Using this paradigm, we measure calcium responses of naturalistic and ChR2-evoked muscle contractions in vivo in crawling C. elegans. We systematically compare the RCaMP sensors to R-GEC01, in terms of action potential-evoked fluorescence increases in neurons, photobleaching, and photoswitching. R-GECO1 displays higher Ca2+ affinity and larger dynamic range than RCaMe but exhibits significant photoactivation with blue and green light, suggesting that integrated channelrhodopsin-based optogenetics using R-GECO1 may be subject to artifact. Finally, we create and test blue, cyan, and yellow variants engineered from GCaMP by rational design. This engineered set of chromatic variants facilitates new experiments in functional imaging and optogenetics."],["dc.identifier.doi","10.3389/fnmol.2013.00002"],["dc.identifier.isi","000209202800001"],["dc.identifier.pmid","23459413"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/10686"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/31433"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Frontiers Media Sa"],["dc.relation.issn","1662-5099"],["dc.rights","CC BY 3.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/3.0"],["dc.title","Genetically encoded calcium indicators for multi-color neural activity imaging and combination with optogenetics"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]