Tatenhorst, Lars

[["dc.bibliographiccitation.artnumber","e1811"],["dc.bibliographiccitation.journal","Cell Death and Disease"],["dc.bibliographiccitation.volume","6"],["dc.contributor.author","Koch, J. C."],["dc.contributor.author","Bitow, F."],["dc.contributor.author","Haack, J."],["dc.contributor.author","D'Hedouville, Z."],["dc.contributor.author","Zhang, J-N"],["dc.contributor.author","Tönges, L."],["dc.contributor.author","Michel, U."],["dc.contributor.author","Oliveira, L. M. A."],["dc.contributor.author","Jovin, T. M."],["dc.contributor.author","Liman, Jan"],["dc.contributor.author","Tatenhorst, L."],["dc.contributor.author","Bähr, M."],["dc.contributor.author","Lingor, P."],["dc.date.accessioned","2017-09-07T11:43:42Z"],["dc.date.available","2017-09-07T11:43:42Z"],["dc.date.issued","2015"],["dc.description.abstract","Many neuropathological and experimental studies suggest that the degeneration of dopaminergic terminals and axons precedes the demise of dopaminergic neurons in the substantia nigra, which finally results in the clinical symptoms of Parkinson disease (PD). The mechanisms underlying this early axonal degeneration are, however, still poorly understood. Here, we examined the effects of overexpression of human wildtype alpha-synuclein (alpha Syn-WT), a protein associated with PD, and its mutant variants alpha Syn-A30P and -A53T on neurite morphology and functional parameters in rat primary midbrain neurons (PMN). Moreover, axonal degeneration after overexpression of alpha Syn-WT and -A30P was analyzed by live imaging in the rat optic nerve in vivo. We found that overexpression of alpha Syn-WT and of its mutants A30P and A53T impaired neurite outgrowth of PMN and affected neurite branching assessed by Sholl analysis in a variant-dependent manner. Surprisingly, the number of primary neurites per neuron was increased in neurons transfected with alpha Syn. Axonal vesicle transport was examined by live imaging of PMN co-transfected with EGFP-labeled synaptophysin. Overexpression of all alpha Syn variants significantly decreased the number of motile vesicles and decelerated vesicle transport compared with control. Macroautophagic flux in PMN was enhanced by alpha Syn-WT and -A53T but not by alpha Syn-A30P. Correspondingly, colocalization of alpha Syn and the autophagy marker LC3 was reduced for alpha Syn-A30P compared with the other alpha Syn variants. The number of mitochondria colocalizing with LC3 as a marker for mitophagy did not differ among the groups. In the rat optic nerve, both alpha Syn-WT and -A30P accelerated kinetics of acute axonal degeneration following crush lesion as analyzed by in vivo live imaging. We conclude that alpha Syn overexpression impairs neurite outgrowth and augments axonal degeneration, whereas axonal vesicle transport and autophagy are severely altered."],["dc.description.sponsorship","Open-Access Publikationsfonds 2015"],["dc.identifier.doi","10.1038/cddis.2015.169"],["dc.identifier.gro","3141868"],["dc.identifier.isi","000358788800011"],["dc.identifier.pmid","26158517"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/12015"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/1967"],["dc.language.iso","en"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.issn","2041-4889"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject","Central nervous system; Molecular neuroscience; Parkinson's disease"],["dc.title","Alpha-Synuclein affects neurite morphology, autophagy, vesicle transport and axonal degeneration in CNS neurons"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","685"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","Molecular Neurobiology"],["dc.bibliographiccitation.lastpage","697"],["dc.bibliographiccitation.volume","57"],["dc.contributor.author","Balke, Dirk"],["dc.contributor.author","Tatenhorst, Lars"],["dc.contributor.author","Dambeck, Vivian"],["dc.contributor.author","Ribas, Vinicius Toledo"],["dc.contributor.author","Vahsen, Björn F."],["dc.contributor.author","Michel, Uwe"],["dc.contributor.author","Bähr, Mathias"],["dc.contributor.author","Lingor, Paul"],["dc.date.accessioned","2020-12-10T14:14:28Z"],["dc.date.available","2020-12-10T14:14:28Z"],["dc.date.issued","2019"],["dc.identifier.doi","10.1007/s12035-019-01744-0"],["dc.identifier.eissn","1559-1182"],["dc.identifier.issn","0893-7648"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/71353"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.title","AAV-Mediated Expression of Dominant-Negative ULK1 Increases Neuronal Survival and Enhances Motor Performance in the MPTP Mouse Model of Parkinson’s Disease"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","jnc.15461"],["dc.bibliographiccitation.firstpage","554"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","Journal of Neurochemistry"],["dc.bibliographiccitation.lastpage","573"],["dc.bibliographiccitation.volume","159"],["dc.contributor.affiliation","Dauer née Joppe, Karina; 1Department of Neurology University Medical Center Goettingen Goettingen Germany"],["dc.contributor.affiliation","Caldi Gomes, Lucas; 1Department of Neurology University Medical Center Goettingen Goettingen Germany"],["dc.contributor.affiliation","Zhang, Shuyu; 3Department of Neurology School of Medicine University Hospital rechts der IsarTechnical University of Munich Munich Germany"],["dc.contributor.affiliation","Parvaz, Mojan; 3Department of Neurology School of Medicine University Hospital rechts der IsarTechnical University of Munich Munich Germany"],["dc.contributor.affiliation","Carboni, Eleonora; 1Department of Neurology University Medical Center Goettingen Goettingen Germany"],["dc.contributor.affiliation","Roser, Anna‐Elisa; 1Department of Neurology University Medical Center Goettingen Goettingen Germany"],["dc.contributor.affiliation","El DeBakey, Hazem; 4Department of Neurology University Hospital of Wuerzburg Wuerzburg Germany"],["dc.contributor.affiliation","Bähr, Mathias; 1Department of Neurology University Medical Center Goettingen Goettingen Germany"],["dc.contributor.affiliation","Vogel‐Mikuš, Katarina; 6Biotechnical faculty University of Ljubljana Ljubljana Slovenia"],["dc.contributor.affiliation","Wang Ip, Chi; 4Department of Neurology University Hospital of Wuerzburg Wuerzburg Germany"],["dc.contributor.affiliation","Becker, Stefan; 8Department of NMR Based Structural BiologyMax Planck Institute for Biophysical Chemistry Goettingen Germany"],["dc.contributor.affiliation","Zweckstetter, Markus; 1Department of Neurology University Medical Center Goettingen Goettingen Germany"],["dc.contributor.author","Tatenhorst, Lars"],["dc.contributor.author","Caldi Gomes, Lucas"],["dc.contributor.author","Zhang, Shuyu"],["dc.contributor.author","Parvaz, Mojan"],["dc.contributor.author","Carboni, Eleonora"],["dc.contributor.author","Roser, Anna‐Elisa"],["dc.contributor.author","El DeBakey, Hazem"],["dc.contributor.author","Bähr, Mathias"],["dc.contributor.author","Lingor, Paul"],["dc.contributor.author","Dauer née Joppe, Karina"],["dc.contributor.author","Vogel‐Mikuš, Katarina"],["dc.contributor.author","Wang Ip, Chi"],["dc.contributor.author","Becker, Stefan"],["dc.contributor.author","Zweckstetter, Markus"],["dc.date.accessioned","2021-07-05T14:57:43Z"],["dc.date.available","2021-07-05T14:57:43Z"],["dc.date.issued","2021"],["dc.date.updated","2022-03-21T09:42:08Z"],["dc.description.abstract","Abstract Regional iron accumulation and α‐synuclein (α‐syn) spreading pathology within the central nervous system are common pathological findings in Parkinson's disease (PD). Whereas iron is known to bind to α‐syn, facilitating its aggregation and regulating α‐syn expression, it remains unclear if and how iron also modulates α‐syn spreading. To elucidate the influence of iron on the propagation of α‐syn pathology, we investigated α‐syn spreading after stereotactic injection of α‐syn preformed fibrils (PFFs) into the striatum of mouse brains after neonatal brain iron enrichment. C57Bl/6J mouse pups received oral gavage with 60, 120, or 240 mg/kg carbonyl iron or vehicle between postnatal days 10 and 17. At 12 weeks of age, intrastriatal injections of 5‐µg PFFs were performed to induce seeding of α‐syn aggregates. At 90 days post‐injection, PFFs‐injected mice displayed long‐term memory deficits, without affection of motor behavior. Interestingly, quantification of α‐syn phosphorylated at S129 showed reduced α‐syn pathology and attenuated spreading to connectome‐specific brain regions after brain iron enrichment. Furthermore, PFFs injection caused intrastriatal microglia accumulation, which was alleviated by iron in a dose‐dependent way. In primary cortical neurons in a microfluidic chamber model in vitro, iron application did not alter trans‐synaptic α‐syn propagation, possibly indicating an involvement of non‐neuronal cells in this process. Our study suggests that α‐syn PFFs may induce cognitive deficits in mice independent of iron. However, a redistribution of α‐syn aggregate pathology and reduction of striatal microglia accumulation in the mouse brain may be mediated via iron‐induced alterations of the brain connectome. image"],["dc.description.abstract","Brain iron accumulation and α‐synuclein (α‐syn) spreading pathology are common pathological findings in Parkinson's disease. To elucidate the influence of iron on α‐syn propagation, we investigated α‐syn spreading after stereotactic injection of α‐syn preformed fibrils (PFFs) into the striatum of C57Bl/6 mice after neonatal brain iron enrichment. 90 days post‐injection, PFFs injected mice displayed memory deficits, reduced α‐syn pathology and spreading to connectome‐specific regions after brain iron enrichment. Our study suggests that α‐syn PFFs may induce cognitive deficits in mice independent of iron. However, a redistribution of α‐syn pathology may be mediated via iron‐induced alterations of the brain connectome. image"],["dc.description.sponsorship","Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659"],["dc.description.sponsorship","MPI"],["dc.identifier.doi","10.1111/jnc.15461"],["dc.identifier.pmid","34176164"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/87716"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/315"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-441"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation.eissn","1471-4159"],["dc.relation.issn","0022-3042"],["dc.relation.workinggroup","RG Bähr (Neurobiological Research Laboratory)"],["dc.rights","This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made."],["dc.title","Brain iron enrichment attenuates α‐synuclein spreading after injection of preformed fibrils"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","3355"],["dc.bibliographiccitation.issue","11"],["dc.bibliographiccitation.journal","Brain"],["dc.bibliographiccitation.lastpage","3370"],["dc.bibliographiccitation.volume","135"],["dc.contributor.author","Tönges, L."],["dc.contributor.author","Frank, T."],["dc.contributor.author","Tatenhorst, L."],["dc.contributor.author","Saal, K. A."],["dc.contributor.author","Koch, J. C."],["dc.contributor.author","Szego, E. M."],["dc.contributor.author","Bähr, M."],["dc.contributor.author","Weishaupt, J. H."],["dc.contributor.author","Lingor, P."],["dc.date.accessioned","2017-09-07T11:48:22Z"],["dc.date.available","2017-09-07T11:48:22Z"],["dc.date.issued","2012"],["dc.description.abstract","Axonal degeneration is one of the earliest features of Parkinson's disease pathology, which is followed by neuronal death in the substantia nigra and other parts of the brain. Inhibition of axonal degeneration combined with cellular neuroprotection therefore seem key to targeting an early stage in Parkinson's disease progression. Based on our previous studies in traumatic and neurodegenerative disease models, we have identified rho kinase as a molecular target that can be manipulated to disinhibit axonal regeneration and improve survival of lesioned central nervous system neurons. In this study, we examined the neuroprotective potential of pharmacological rho kinase inhibition mediated by fasudil in the in vitro 1-methyl-4-phenylpyridinium cell culture model and in the subchronic in vivo 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. Application of fasudil resulted in a significant attenuation of dopaminergic cell loss in both paradigms. Furthermore, dopaminergic terminals were preserved as demonstrated by analysis of neurite network in vitro, striatal fibre density and by neurochemical analysis of the levels of dopamine and its metabolites in the striatum. Behavioural tests demonstrated a clear improvement in motor performance after fasudil treatment. The Akt survival pathway was identified as an important molecular mediator for neuroprotective effects of rho kinase inhibition in our paradigm. We conclude that inhibition of rho kinase using the clinically approved small molecule inhibitor fasudil may be a promising new therapeutic strategy for Parkinson's disease."],["dc.identifier.doi","10.1093/brain/aws254"],["dc.identifier.gro","3142444"],["dc.identifier.isi","000311644800021"],["dc.identifier.pmid","23087045"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/9499"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/8352"],["dc.language.iso","en"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.issn","0006-8950"],["dc.rights","CC BY-NC 3.0"],["dc.rights.uri","https://creativecommons.org/licenses/by-nc/3.0"],["dc.title","Inhibition of rho kinase enhances survival of dopaminergic neurons and attenuates axonal loss in a mouse model of Parkinson's disease"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1"],["dc.bibliographiccitation.journal","Pharmacology & Therapeutics"],["dc.bibliographiccitation.lastpage","21"],["dc.bibliographiccitation.volume","189"],["dc.contributor.author","Koch, Jan Christoph"],["dc.contributor.author","Tatenhorst, Lars"],["dc.contributor.author","Roser, Anna-Elisa"],["dc.contributor.author","Saal, Kim-Ann"],["dc.contributor.author","Tönges, Lars"],["dc.contributor.author","Lingor, Paul"],["dc.date.accessioned","2020-12-10T15:20:44Z"],["dc.date.available","2020-12-10T15:20:44Z"],["dc.date.issued","2018"],["dc.identifier.doi","10.1016/j.pharmthera.2018.03.008"],["dc.identifier.issn","0163-7258"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/72778"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.title","ROCK inhibition in models of neurodegeneration and its potential for clinical translation"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","309"],["dc.bibliographiccitation.issue","2-3"],["dc.bibliographiccitation.journal","NeuroMolecular Medicine"],["dc.bibliographiccitation.lastpage","321"],["dc.bibliographiccitation.volume","19"],["dc.contributor.author","Carboni, Eleonora"],["dc.contributor.author","Tatenhorst, Lars"],["dc.contributor.author","Tönges, Lars"],["dc.contributor.author","Barski, Elisabeth"],["dc.contributor.author","Dambeck, Vivian"],["dc.contributor.author","Bähr, Mathias"],["dc.contributor.author","Lingor, Paul"],["dc.date.accessioned","2018-04-23T11:49:32Z"],["dc.date.available","2018-04-23T11:49:32Z"],["dc.date.issued","2017"],["dc.description.abstract","Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, and its causes remain unknown. A major hallmark of the disease is the increasing presence of aggregated alpha-synuclein (aSyn). Furthermore, there is a solid consensus on iron (Fe) accumulation in several regions of PD brains during disease progression. In our study, we focused on the interaction of Fe and aggregating aSyn in vivo in a transgenic mouse model overexpressing human aSyn bearing the A53T mutation (prnp.aSyn.A53T). We utilized a neonatal iron-feeding model to exacerbate the motor phenotype of the transgenic mouse model. Beginning from day 100, mice were treated with deferiprone (DFP), a ferric chelator that is able to cross the blood–brain barrier and is currently used in clinics as treatment for hemosiderosis. Our paradigm resulted in an impairment of the learning abilities in the rotarod task and the novel object recognition test. DFP treatment significantly improved the performance in both tasks. Although this was not accompanied by alterations in aSyn aggregation, our results support DFP as possible therapeutic option in PD."],["dc.identifier.doi","10.1007/s12017-017-8447-9"],["dc.identifier.gro","3142070"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/13724"],["dc.language.iso","en"],["dc.notes.intern","lifescience updates Crossref Import"],["dc.notes.status","final"],["dc.relation.issn","1535-1084"],["dc.title","Deferiprone Rescues Behavioral Deficits Induced by Mild Iron Exposure in a Mouse Model of Alpha-Synuclein Aggregation"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.peerReviewed","no"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Frontiers in Neuroscience"],["dc.bibliographiccitation.volume","15"],["dc.contributor.author","Martinez Hernandez, Ana"],["dc.contributor.author","Silbern, Ivan"],["dc.contributor.author","Geffers, Insa"],["dc.contributor.author","Tatenhorst, Lars"],["dc.contributor.author","Becker, Stefan"],["dc.contributor.author","Urlaub, Henning"],["dc.contributor.author","Zweckstetter, Markus"],["dc.contributor.author","Griesinger, Christian"],["dc.contributor.author","Eichele, Gregor"],["dc.date.accessioned","2021-08-12T07:45:45Z"],["dc.date.available","2021-08-12T07:45:45Z"],["dc.date.issued","2021"],["dc.description.abstract","α-synuclein (αSyn) is the main protein component of Lewy bodies, intracellular inclusions found in the brain of Parkinson’s disease (PD) patients. Neurotoxic αSyn species are broadly modified post-translationally and, in patients with genetic forms of PD, carry genetically encoded amino acid substitutions. Mutations and C-terminal truncation can increase αSyn oligomerization and fibrillization. Although several genetic mouse models based on αSyn mutations and/or truncations exist, there is still a lack of mouse models for synucleinopathies not relying on overexpression. We report here two synucleinopathy mouse models, which are based on a triple alanine to proline mutation and a C-terminal truncation of αSyn, but do not overexpress the mutant protein when compared to the endogenous mouse protein. We knocked h αSyn TP or h αSyn Δ119 (h stands for “human”) into the murine αSyn locus. hαSyn TP is a structure-based mutant with t riple alanine to p roline substitutions that favors oligomers, is neurotoxic and evokes PD-like symptoms in Drosophila melanogaster . hαSyn Δ119 lacks 21 amino acids at the C-terminus, favors fibrillary aggregates and occurs in PD. Knocking-in of h αSyn TP or h αSyn Δ119 into the murine αSyn locus places the mutant protein under the control of the endogenous regulatory elements while simultaneously disrupting the mαSyn gene. Mass spectrometry revealed that h αSyn TP and h αSyn Δ119 mice produced 12 and 10 times less mutant protein, compared to mαSyn in wild type mice. We show phenotypes in 1 and 1.5 years old hαSyn TP and hαSyn Δ119 mice, despite the lower levels of hαSyn TP and hαSyn Δ119 expression. Direct comparison of the two mouse models revealed many commonalities but also aspects unique to each model. Commonalities included strong immunoactive state, impaired olfaction and motor coordination deficits. Neither model showed DAergic neuronal loss. Impaired climbing abilities at 1 year of age and a deviant gait pattern at 1.5 years old were specific for hαSyn Δ119 mice, while a compulsive behavior was exclusively detected in hαSyn TP mice starting at 1 year of age. We conclude that even at very moderate levels of expression the two αSyn variants evoke measurable and progressive deficiencies in mutant mice. The two transgenic mouse models can thus be suitable to study αSyn-variant-based pathology in vivo and test new therapeutic approaches."],["dc.description.abstract","α-synuclein (αSyn) is the main protein component of Lewy bodies, intracellular inclusions found in the brain of Parkinson’s disease (PD) patients. Neurotoxic αSyn species are broadly modified post-translationally and, in patients with genetic forms of PD, carry genetically encoded amino acid substitutions. Mutations and C-terminal truncation can increase αSyn oligomerization and fibrillization. Although several genetic mouse models based on αSyn mutations and/or truncations exist, there is still a lack of mouse models for synucleinopathies not relying on overexpression. We report here two synucleinopathy mouse models, which are based on a triple alanine to proline mutation and a C-terminal truncation of αSyn, but do not overexpress the mutant protein when compared to the endogenous mouse protein. We knocked h αSyn TP or h αSyn Δ119 (h stands for “human”) into the murine αSyn locus. hαSyn TP is a structure-based mutant with t riple alanine to p roline substitutions that favors oligomers, is neurotoxic and evokes PD-like symptoms in Drosophila melanogaster . hαSyn Δ119 lacks 21 amino acids at the C-terminus, favors fibrillary aggregates and occurs in PD. Knocking-in of h αSyn TP or h αSyn Δ119 into the murine αSyn locus places the mutant protein under the control of the endogenous regulatory elements while simultaneously disrupting the mαSyn gene. Mass spectrometry revealed that h αSyn TP and h αSyn Δ119 mice produced 12 and 10 times less mutant protein, compared to mαSyn in wild type mice. We show phenotypes in 1 and 1.5 years old hαSyn TP and hαSyn Δ119 mice, despite the lower levels of hαSyn TP and hαSyn Δ119 expression. Direct comparison of the two mouse models revealed many commonalities but also aspects unique to each model. Commonalities included strong immunoactive state, impaired olfaction and motor coordination deficits. Neither model showed DAergic neuronal loss. Impaired climbing abilities at 1 year of age and a deviant gait pattern at 1.5 years old were specific for hαSyn Δ119 mice, while a compulsive behavior was exclusively detected in hαSyn TP mice starting at 1 year of age. We conclude that even at very moderate levels of expression the two αSyn variants evoke measurable and progressive deficiencies in mutant mice. The two transgenic mouse models can thus be suitable to study αSyn-variant-based pathology in vivo and test new therapeutic approaches."],["dc.identifier.doi","10.3389/fnins.2021.643391"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/88545"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/313"],["dc.identifier.url","https://sfb1286.uni-goettingen.de/literature/publications/126"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-448"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation","SFB 1286: Quantitative Synaptologie"],["dc.relation","SFB 1286 | A06: Mitochondrienfunktion und -umsatz in Synapsen"],["dc.relation.eissn","1662-453X"],["dc.relation.workinggroup","RG Griesinger"],["dc.relation.workinggroup","RG Urlaub (Bioanalytische Massenspektrometrie)"],["dc.rights","http://creativecommons.org/licenses/by/4.0/"],["dc.title","Low-Expressing Synucleinopathy Mouse Models Based on Oligomer-Forming Mutations and C-Terminal Truncation of α-Synuclein"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","2008"],["dc.bibliographiccitation.issue","18"],["dc.bibliographiccitation.journal","The EMBO Journal"],["dc.bibliographiccitation.lastpage","2025"],["dc.bibliographiccitation.volume","35"],["dc.contributor.author","Vingill, Siv"],["dc.contributor.author","Brockelt, David"],["dc.contributor.author","Lancelin, Camille"],["dc.contributor.author","Tatenhorst, Lars"],["dc.contributor.author","Dontcheva, Guergana"],["dc.contributor.author","Preisinger, Christian"],["dc.contributor.author","Schwedhelm-Domeyer, Nicola"],["dc.contributor.author","Joseph, Sabitha"],["dc.contributor.author","Mitkovski, Miso"],["dc.contributor.author","Goebbels, Sandra"],["dc.contributor.author","Nave, Klaus-Armin"],["dc.contributor.author","Schulz, Joerg B."],["dc.contributor.author","Marquardt, Till"],["dc.contributor.author","Lingor, Paul"],["dc.contributor.author","Stegmueller, Judith"],["dc.date.accessioned","2018-11-07T10:08:31Z"],["dc.date.available","2018-11-07T10:08:31Z"],["dc.date.issued","2016"],["dc.description.abstract","Mutations in the FBXO7 (PARK15) gene have been implicated in a juvenile form of parkinsonism termed parkinsonian pyramidal syndrome (PPS), characterized by Parkinsonian symptoms and pyramidal tract signs. FBXO7 (F-box protein only 7) is a subunit of the SCF (SKP1/cullin-1/F-box protein) E3 ubiquitin ligase complex, but its relevance and function in neurons remain to be elucidated. Here, we report that the E3 ligase FBXO7-SCF binds to and ubiquitinates the proteasomal subunit PSMA2. In addition, we show that FBXO7 is a proteasome-associated protein involved in proteasome assembly. In FBXO7 knockout mice, we find reduced proteasome activity and early-onset motor deficits together with premature death. In addition, we demonstrate that NEX (neuronal helix-loop-helix protein-1)-Cre-induced deletion of the FBXO7 gene in forebrain neurons or the loss of FBXO7 in tyrosine hydroxylase (TH)-positive neurons results in motor defects, reminiscent of the phenotype in PARK15 patients. Taken together, our study establishes a vital role for FBXO7 in neurons, which is required for proper motor control and accentuates the importance of FBXO7 in proteasome function."],["dc.identifier.doi","10.15252/embj.201593585"],["dc.identifier.isi","000384084900006"],["dc.identifier.pmid","27497298"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/39477"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Wiley-blackwell"],["dc.relation.issn","1460-2075"],["dc.relation.issn","0261-4189"],["dc.title","Loss of FBXO7 (PARK15) results in reduced proteasome activity and models a parkinsonism-like phenotype in mice"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","UNSP 239"],["dc.bibliographiccitation.journal","Frontiers in Aging Neuroscience"],["dc.bibliographiccitation.volume","6"],["dc.contributor.author","Tönges, L."],["dc.contributor.author","Szegö, E. M."],["dc.contributor.author","Hause, P."],["dc.contributor.author","Saal, K.-A."],["dc.contributor.author","Tatenhorst, L."],["dc.contributor.author","Koch, J. C."],["dc.contributor.author","D'Hedouville, Z."],["dc.contributor.author","Dambeck, V."],["dc.contributor.author","Kügler, Sebastian"],["dc.contributor.author","Dohm, C. P."],["dc.contributor.author","Bähr, M."],["dc.contributor.author","Lingor, P."],["dc.date.accessioned","2017-09-07T11:45:32Z"],["dc.date.available","2017-09-07T11:45:32Z"],["dc.date.issued","2014"],["dc.description.abstract","The dopaminergic (DAergic) nigrostriatal tract has an intrinsic regenerative capacity which can be impaired in Parkinson's disease (PD). Alpha-synuclein (aSyn) is a major pathogenic component in PD but its impact on DAergic axonal regeneration is largely unknown. In this study, we expressed pathogenic variants of human aSyn by means of recombinant adeno-associated viral vectors in experimental paradigms of DAergic regeneration. In a scratch lesion model in vitro, both aSyn(A30P) and aSyn(A53T) significantly reduced DAergic neurite regeneration and induced loss of TH-immunopositive cells while aSyn(WT) showed only minor cellular neurotoxic effects. The striatal density of TH-immunopositive axons in the striatal 6-OHDA lesion mouse model was attenuated only by aSyn(A30P). However, striatal expression levels of the regeneration marker GAP-43 in TH-immunopositive fibers were reduced by both aSyn(A30P) and aSyn(A53T), but not by aSyn(WT), which was associated with an activation of the ROCK signaling pathway. Nigral DAergic cell loss was only mildly enhanced by additional overexpression of aSyn variants. Our findings indicate that mutations of aSyn have a strong impact on the regenerative capacity of DAergic neurons, which may contribute to their pathogenic effects."],["dc.description.sponsorship","Open-Access Publikationsfonds 2014"],["dc.format.extent","10"],["dc.identifier.doi","10.3389/fnagi.2014.00239"],["dc.identifier.gro","3142053"],["dc.identifier.isi","000341696200001"],["dc.identifier.pmid","25309425"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/10893"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/4023"],["dc.language.iso","en"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.issn","1663-4365"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Alpha-synuclein mutations impair axonal regeneration in models of Parkinson's disease"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","39"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Acta Neuropathologica Communication"],["dc.bibliographiccitation.volume","4"],["dc.contributor.author","Tatenhorst, Lars"],["dc.contributor.author","Eckermann, Katrin"],["dc.contributor.author","Dambeck, Vivian"],["dc.contributor.author","Fonseca-Ornelas, Luis"],["dc.contributor.author","Walle, Hagen"],["dc.contributor.author","Lopes Da Fonseca, Tomás"],["dc.contributor.author","Koch, Jan C."],["dc.contributor.author","Becker, Stefan"],["dc.contributor.author","Tönges, Lars"],["dc.contributor.author","Bähr, Mathias"],["dc.contributor.author","Outeiro, Tiago F."],["dc.contributor.author","Zweckstetter, Markus"],["dc.contributor.author","Lingor, Paul"],["dc.date.accessioned","2018-02-22T13:45:16Z"],["dc.date.available","2018-02-22T13:45:16Z"],["dc.date.issued","2016"],["dc.description.abstract","Parkinson's disease (PD) is the most common neurodegenerative movement disorder, yet disease-modifying treatments do not currently exist. Rho-associated protein kinase (ROCK) was recently described as a novel neuroprotective target in PD. Since alpha-synuclein (α-Syn) aggregation is a major hallmark in the pathogenesis of PD, we aimed to evaluate the anti-aggregative potential of pharmacological ROCK inhibition using the isoquinoline derivative Fasudil, a small molecule inhibitor already approved for clinical use in humans. Fasudil treatment significantly reduced α-Syn aggregation in vitro in a H4 cell culture model as well as in a cell-free assay. Nuclear magnetic resonance spectroscopy analysis revealed a direct binding of Fasudil to tyrosine residues Y133 and Y136 in the C-terminal region of α-Syn. Importantly, this binding was shown to be biologically relevant using site-directed mutagenesis of these residues in the cell culture model. Furthermore, we evaluated the impact of long-term Fasudil treatment on α-Syn pathology in vivo in a transgenic mouse model overexpressing human α-Syn bearing the A53T mutation (α-Syn(A53T) mice). Fasudil treatment improved motor and cognitive functions in α-Syn(A53T) mice as determined by Catwalk(TM) gait analysis and novel object recognition (NOR), without apparent side effects. Finally, immunohistochemical analysis revealed a significant reduction of α-Syn pathology in the midbrain of α-Syn(A53T) mice after Fasudil treatment. Our results demonstrate that Fasudil, next to its effects mediated by ROCK-inhibition, directly interacts with α-Syn and attenuates α-Syn pathology. This underscores the translational potential of Fasudil as a disease-modifying drug for the treatment of PD and other synucleinopathies."],["dc.identifier.doi","10.1186/s40478-016-0310-y"],["dc.identifier.pmid","27101974"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/13225"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/12432"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","final"],["dc.relation.doi","10.1186/s40478-016-0310-y"],["dc.relation.eissn","2051-5960"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Fasudil attenuates aggregation of α-synuclein in models of Parkinson's disease"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]