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.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"]]