Saal, Kim-Ann

[["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.artnumber","304"],["dc.bibliographiccitation.journal","Frontiers in Neuroscience"],["dc.bibliographiccitation.volume","8"],["dc.contributor.author","Günther, R."],["dc.contributor.author","Saal, K.-A."],["dc.contributor.author","Suhr, M."],["dc.contributor.author","Scheer, D."],["dc.contributor.author","Koch, J. C."],["dc.contributor.author","Bähr, M."],["dc.contributor.author","Lingor, P."],["dc.contributor.author","Tönges, L."],["dc.date.accessioned","2017-09-07T11:45:27Z"],["dc.date.available","2017-09-07T11:45:27Z"],["dc.date.issued","2014"],["dc.description.abstract","Disease progression in amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motoneurons and their axons which results in a progressive muscle weakness and ultimately death from respiratory failure. The only approved drug, riluzole, lacks clinical efficacy so that more potent treatment options are needed. We have identified rho kinase (ROCK) as a target, which can be manipulated to beneficially influence disease progression in models of ALS. Here, we examined the therapeutic potential of the ROCK inhibitor Y-27632 in both an in vitro and in an in vivo paradigm of motoneuron disease. Application of Y-27632 to primary motoneurons in vitro increased survival and promoted neunte outgrowth. In vivo, SOD1G93A mice were orally treated with 2 or 30 mg/kg body weight of Y-27632. The 2 mg/kg group did not benefit from Y-27632 treatment, whereas treatment with 30 mg/kg resulted in improved motor function in male mice. Female mice showed only limited improvement and overall survival was not modified in both 2 and 30 mg/kg Y-27632 groups. In conclusion, we provide evidence that inhibition of ROCK by Y-27632 is neuroprotective in vitro but has limited beneficial effects in vivo being restricted to male mice. Therefore, the evaluation of ROCK inhibitors in preclinical models of ALS should always take gender differences into account."],["dc.format.extent","9"],["dc.identifier.doi","10.3389/fnins.2014.00304"],["dc.identifier.gro","3142033"],["dc.identifier.isi","000346516800001"],["dc.identifier.pmid","25339858"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/11029"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/3801"],["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","1662-453X"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","The rho kinase inhibitor Y-27632 improves motor performance in male SOD1(G93A) mice"],["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","12247"],["dc.bibliographiccitation.issue","12"],["dc.bibliographiccitation.journal","ACS Nano"],["dc.bibliographiccitation.lastpage","12254"],["dc.bibliographiccitation.volume","2018"],["dc.contributor.author","Saal, Kim-A."],["dc.contributor.author","Richter, Frank"],["dc.contributor.author","Rehling, Peter"],["dc.contributor.author","Rizzoli, Silvio O."],["dc.date.accessioned","2019-07-09T11:50:22Z"],["dc.date.available","2019-07-09T11:50:22Z"],["dc.date.issued","2018"],["dc.description.abstract","Recent advances in optical nanoscopy have brought the imaging resolution to the size of the individual macromolecules, thereby setting stringent requirements for the fluorescent labels. Such requirements are optimally fulfilled by the incorporation of unnatural amino acids (UAAs) in the proteins of interest (POI), followed by fluorophore conjugation via click chemistry. However, this approach has been limited to single POIs in mammalian cells. Here we solve this problem by incorporating different UAAs in different POIs, which are expressed in independent cell sets. The cells are then fused, thereby combining the different proteins and organelles, and are easily imaged by dual-color super-resolution microscopy. This procedure, which we termed Fuse2Click, is simple, requires only the well-established Amber codon, and allows the use of all previously optimized UAAs and tRNA/RS pairs. This should render it a tool of choice for multi-color click-based imaging."],["dc.identifier.doi","10.1021/acsnano.8b06047"],["dc.identifier.pmid","30525434"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15921"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59757"],["dc.identifier.url","https://sfb1190.med.uni-goettingen.de/production/literature/publications/47"],["dc.identifier.url","https://sfb1286.uni-goettingen.de/literature/publications/2"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation","info:eu-repo/grantAgreement/EC/FP7/614765/EU//NEUROMOLANATOMY"],["dc.relation","info:eu-repo/grantAgreement/EC/FP7/339580/EU//MITRAC"],["dc.relation","SFB 1190: Transportmaschinen und Kontaktstellen zellulärer Kompartimente"],["dc.relation","SFB 1190 | P09: Proteinsortierung in der Synapse: Prinzipien und molekulare Organisation"],["dc.relation","SFB 1286: Quantitative Synaptologie"],["dc.relation","SFB 1286 | A06: Mitochondrienfunktion und -umsatz in Synapsen"],["dc.relation.issn","1936-086X"],["dc.relation.workinggroup","RG Rehling (Mitochondrial Protein Biogenesis)"],["dc.relation.workinggroup","RG Rizzoli (Quantitative Synaptology in Space and Time)"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.subject.ddc","573"],["dc.subject.ddc","612"],["dc.title","Combined Use of Unnatural Amino Acids Enables Dual Color Super-Resolution Imaging of Proteins via Click Chemistry"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["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","13"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Brain Pathology"],["dc.bibliographiccitation.lastpage","25"],["dc.bibliographiccitation.volume","27"],["dc.contributor.author","Saal, Kim-Ann"],["dc.contributor.author","Galter, Dagmar"],["dc.contributor.author","Roeber, Sigrun"],["dc.contributor.author","Bähr, Mathias"],["dc.contributor.author","Tönges, Lars"],["dc.contributor.author","Lingor, Paul"],["dc.date.accessioned","2018-02-22T13:10:28Z"],["dc.date.available","2018-02-22T13:10:28Z"],["dc.date.issued","2017"],["dc.description.abstract","Causative treatment strategies for Parkinson's disease (PD) will have to address multiple underlying pathomechanisms to attenuate neurodegeneration. Additionally, the intrinsic regenerative capacity of the central nervous system is also an important factor contributing to restoration. Extracellular cues can limit sprouting and regrowth of adult neurons, but even aged neurons have a low intrinsic regeneration capacity. Whether this capacity has been lost or if growth inhibitory cues are increased during PD progression has not been resolved yet. In this study, we assessed the regenerative potential in the nigrostriatal system in post-mortem brain sections of PD patients compared to age-matched and young controls. Investigation of the expression pattern of the regeneration-associated protein GAP-43 suggested a lower regenerative capacity in nigral dopaminergic neurons of PD patients. Furthermore, the increase in protein expression of the growth-inhibitory protein ROCK2 in astrocytes and a similar trend in microglia, suggests an important role for ROCK2 in glial PD pathology, which is initiated already in normal aging. Considering the role of astro- and microglia in PD pathogenesis as well as beneficial effects of ROCK inhibition on neuronal survival and regeneration in neurodegenerative disease models, our data strengthens the importance of the ROCK pathway as a therapeutic target in PD."],["dc.identifier.doi","10.1111/bpa.12346"],["dc.identifier.pmid","26748453"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/12431"],["dc.language.iso","en"],["dc.notes.status","final"],["dc.relation.doi","10.1111/bpa.12346"],["dc.relation.eissn","1750-3639"],["dc.relation.issn","1015-6305"],["dc.title","Altered Expression of Growth Associated Protein-43 and Rho Kinase in Human Patients with Parkinson's Disease"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","217"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","Glia"],["dc.bibliographiccitation.lastpage","232"],["dc.bibliographiccitation.volume","62"],["dc.contributor.author","Tönges, L."],["dc.contributor.author","Günther, R."],["dc.contributor.author","Suhr, M."],["dc.contributor.author","Jansen, J."],["dc.contributor.author","Balck, A."],["dc.contributor.author","Saal, K.-A."],["dc.contributor.author","Barski, E."],["dc.contributor.author","Nientied, T."],["dc.contributor.author","Götz, A. A."],["dc.contributor.author","Koch, J.-C."],["dc.contributor.author","Mueller, B. K."],["dc.contributor.author","Weishaupt, J. H."],["dc.contributor.author","Sereda, M. W."],["dc.contributor.author","Hanisch, U.-K."],["dc.contributor.author","Bähr, M."],["dc.contributor.author","Lingor, P."],["dc.date.accessioned","2017-09-07T11:46:53Z"],["dc.date.available","2017-09-07T11:46:53Z"],["dc.date.issued","2014"],["dc.description.abstract","Disease progression in amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motoneurons (MN) and their axons, but is also influenced by neighboring cells such as astrocytes and microglial cells. The role of microglia in ALS is complex as it switches from an anti-inflammatory and neuroprotective phenotype in early disease to a proinflammatory and neurotoxic phenotype in later stages. Our previous studies in models of neurodegeneration identified rho kinase (ROCK) as a target, which can be manipulated to beneficially influence disease progression. Here, we examined the neuroprotective potential of the ROCK inhibitor Fasudil to target the central pathogenic features of ALS. Application of Fasudil to kainic acid-lesioned primary MN in vitro resulted in a strong prosurvival effect. In vivo, SOD1(G93A) mice benefited from oral treatment with Fasudil showing prolonged survival and improved motor function. These findings were correlated to an improved survival of motor neurons and a pronounced alteration of astroglial and microglial cell infiltration of the spinal cord under Fasudil treatment. Modeling a proinflammatory microglial phenotype by stimulation with LPS in vitro, Fasudil decreased the release of proinflammatory cytokines and chemokines TNF, Il6, CCL2, CCL3, and CCL5 while CXCL1 release was only transiently suppressed. In sciatic nerve motor axons, neuromuscular junction remodeling processes were increased. In conclusion, we provide preclinical and neurobiological evidence that inhibition of ROCK by the clinically approved small molecule inhibitor Fasudil may be a novel therapeutic approach in ALS combining both neuroprotection and immunomodulation for the cure of this devastating disease. GLIA 2014;62:217-232"],["dc.identifier.doi","10.1002/glia.22601"],["dc.identifier.gro","3142195"],["dc.identifier.isi","000328209300005"],["dc.identifier.pmid","24311453"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/5588"],["dc.language.iso","en"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.eissn","1098-1136"],["dc.relation.issn","0894-1491"],["dc.title","Rho Kinase Inhibition Modulates Microglia Activation and Improves Survival in a Model of Amyotrophic Lateral Sclerosis"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","3438"],["dc.bibliographiccitation.issue","11"],["dc.bibliographiccitation.journal","Angewandte Chemie (International ed. in English)"],["dc.bibliographiccitation.lastpage","3443"],["dc.bibliographiccitation.volume","58"],["dc.contributor.author","Kabatas, Selda"],["dc.contributor.author","Agüi-Gonzalez, Paola"],["dc.contributor.author","Saal, Kim-Ann"],["dc.contributor.author","Jähne, Sebastian"],["dc.contributor.author","Opazo, Felipe"],["dc.contributor.author","Rizzoli, Silvio O."],["dc.contributor.author","Phan, Nhu T. N."],["dc.date.accessioned","2019-07-09T11:50:32Z"],["dc.date.available","2019-07-09T11:50:32Z"],["dc.date.issued","2019"],["dc.description.abstract","Boron has been employed in materials science as a marker for imaging specific structures by electron energy loss spectroscopy (EELS) or secondary ion mass spectrometry (SIMS). It has a strong potential in biological analyses as well; however, the specific coupling of a sufficient number of boron atoms to a biological structure has proven challenging. Herein, we synthesize tags containing closo-1,2-dicarbadodecaborane, coupled to soluble peptides, which were integrated in specific proteins by click chemistry in mammalian cells and were also coupled to nanobodies for use in immunocytochemistry experiments. The tags were fully functional in biological samples, as demonstrated by nanoSIMS imaging of cell cultures. The boron signal revealed the protein of interest, while other SIMS channels were used for imaging different positive ions, such as the cellular metal ions. This allows, for the first time, the simultaneous imaging of such ions with a protein of interest and will enable new biological applications in the SIMS field."],["dc.identifier.doi","10.1002/anie.201812032"],["dc.identifier.pmid","30614604"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15959"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59792"],["dc.identifier.url","https://sfb1286.uni-goettingen.de/literature/publications/83"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation","info:eu-repo/grantAgreement/EC/FP7/614765/EU//NEUROMOLANATOMY"],["dc.relation","SFB 1286: Quantitative Synaptologie"],["dc.relation","SFB 1286 | B01: Der Verteilung struktureller Lipide in synaptischen Membranen"],["dc.relation.issn","1521-3773"],["dc.relation.workinggroup","RG Phan"],["dc.relation.workinggroup","RG Rizzoli (Quantitative Synaptology in Space and Time)"],["dc.rights","CC BY-NC-ND 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by-nc-nd/4.0"],["dc.subject.ddc","610"],["dc.title","Boron-Containing Probes for Non-optical High-Resolution Imaging of Biological Samples"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["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.firstpage","150"],["dc.bibliographiccitation.journal","Neurobiology of Disease"],["dc.bibliographiccitation.lastpage","162"],["dc.bibliographiccitation.volume","73"],["dc.contributor.author","Saal, K.-A."],["dc.contributor.author","Koch, J. C."],["dc.contributor.author","Tatenhorst, L."],["dc.contributor.author","Szegő, É. M."],["dc.contributor.author","Ribas, V. T."],["dc.contributor.author","Michel, U."],["dc.contributor.author","Bähr, M."],["dc.contributor.author","Tönges, L."],["dc.contributor.author","Lingor, P."],["dc.date.accessioned","2017-09-07T11:45:21Z"],["dc.date.available","2017-09-07T11:45:21Z"],["dc.date.issued","2015"],["dc.description.abstract","Parkinson's disease (PD) is a neurodegenerative disorder with prominent neuronal cell death in the substantia nigra (SN) and other parts of the brain. Previous studies in models of traumatic and neurodegenerative CNS disease showed that pharmacological inhibition of Rho-associated kinase (ROCK), a molecule involved in inhibitory signaling in the CNS, by small-molecule inhibitors improves neuronal survival and increases regeneration. Most small-molecule inhibitors, however, offer only limited target specificity and also inhibit other kinases, including both ROCK isoforms. To establish the role of the predominantly brain-expressed ROCK2 isoform in models of regeneration and PD, we used adeno-associated viral vectors (MV) to specifically knockdown ROCK2 in neurons. Rat primary midbrain neurons (PMN) were transduced with MV expressing short-hairpin-RNA (shRNA) against ROCK2 and LIM-domain kinase 1 (LIMK1), one of the downstream targets of ROCK2. While knock-down of ROCK2 and LIMK1 both enhanced neurite regeneration in a traumatic scratch lesion model, only ROCK2-shRNA protected PMN against 1-methyl-4-phenylpyridinium (MPP+) toxicity. Moreover, AAV.ROCK2-shRNA increased levels of the pro-survival markers Bcl-2 and phospho-Erk1. In vivo, AAV.ROCK2-shRNA vectors were injected into the ipsilateral SN and a unilateral 6-OHDA striatal lesion was performed. After four weeks, behavioral, immunohistochemical and biochemical alterations were investigated. Downregulation of ROCK2 protected dopaminergic neurons in the SN from 6-OHDA-induced degeneration and resulted in significantly increased TH-positive neuron numbers. This effect, however, was confined to nigral neuronal somata as striatal terminal density, dopamine and metabolite levels were not significantly preserved. Interestingly, motor behavior was improved in the ROCK2-shRNA treated animals compared to control after four weeks. Our studies thus confirm ROCK2 as a promising therapeutic target in models of PD and demonstrate that neuronspecific inhibition of ROCK2 promotes survival of lesioned dopaminergic neurons. (C) 2015 Elsevier Inc All rights reserved."],["dc.identifier.doi","10.1016/j.nbd.2014.09.013"],["dc.identifier.gro","3141993"],["dc.identifier.isi","000346328100014"],["dc.identifier.pmid","25283984"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/3357"],["dc.language.iso","en"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.eissn","1095-953X"],["dc.relation.issn","0969-9961"],["dc.title","AAV.shRNA-mediated downregulation of ROCK2 attenuates degeneration of dopaminergic neurons in toxin-induced models of Parkinson's disease in vitro and in vivo"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","n/a"],["dc.bibliographiccitation.journal","Journal of Neurochemistry"],["dc.bibliographiccitation.lastpage","n/a"],["dc.contributor.author","Saal, Kim Ann"],["dc.contributor.author","Warth Pérez Arias, Carmina"],["dc.contributor.author","Roser, Anna‐Elisa"],["dc.contributor.author","Christoph Koch, Jan"],["dc.contributor.author","Bähr, Mathias"],["dc.contributor.author","Rizzoli, Silvio O."],["dc.contributor.author","Lingor, Paul"],["dc.date.accessioned","2021-04-14T08:30:03Z"],["dc.date.available","2021-04-14T08:30:03Z"],["dc.date.issued","2021"],["dc.description.abstract","Abstract The Rho kinase (ROCK) signaling pathway is an attractive therapeutic target in neurodegeneration since it has been linked to the prevention of neuronal death and neurite regeneration. The isoquinoline derivative fasudil is a potent ROCK inhibitor, which is already approved for chronic clinical treatment in humans. However, the effects of chronic fasudil treatments on neuronal function are still unknown. We analyzed here chronic fasudil treatment in primary rat hippocampal cultures. Neurons were stimulated with 20 Hz field stimulation and we investigated pre‐synaptic mechanisms and parameters regulating synaptic transmission after fasudil treatment by super resolution stimulated emission depletion (STED) microscopy, live‐cell fluorescence imaging, and western blotting. Fasudil did not affect basic synaptic function or the amount of several synaptic proteins, but it altered the chronic dynamics of the synaptic vesicles. Fasudil reduced the proportion of the actively recycling vesicles, and shortened the vesicle lifetime, resulting overall in a reduction of the synaptic response upon stimulation. We conclude that fasudil does not alter synaptic structure, accelerates vesicle turnover, and decreases the number of released vesicles. This broadens the known spectrum of effects of this drug, and suggests new potential clinical uses. image"],["dc.description.abstract","Chronic treatment with the Rho kinase (ROCK) inhibitor fasudil did not affect basic synaptic protein abundance, but altered synaptic vesicles dynamics. In stimulated cultures, fasudil reduced synapsin1 phosphorylation and the size of the recycling pool. We propose that over‐active vesicles thus are degraded faster reducing the synaptic response upon stimulation. This broadens the spectrum of fasudil effects suggesting new clinical uses of this drug. image"],["dc.description.sponsorship","Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659"],["dc.identifier.doi","10.1111/jnc.15274"],["dc.identifier.pmid","33341946"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/83082"],["dc.identifier.url","https://sfb1286.uni-goettingen.de/literature/publications/67"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-399"],["dc.relation","SFB 1286: Quantitative Synaptologie"],["dc.relation","SFB 1286 | B09: Cytoskelettale Veränderungen tragen zu synapto-axonalen Fehlfunktionen in Morbus Parkinson bei"],["dc.relation","SFB 1286 | Z03: Unkomplizierte multispektrale, superauflösende Bildgebung durch zehnfache Expansionsmikroskopie"],["dc.relation.eissn","1471-4159"],["dc.relation.issn","0022-3042"],["dc.relation.workinggroup","RG Rizzoli (Quantitative Synaptology in Space and Time)"],["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","Rho‐kinase inhibition by fasudil modulates pre‐synaptic vesicle dynamics"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]