Tereshchenko, Yuliya

[["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","534"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","Molecular Therapy"],["dc.bibliographiccitation.lastpage","543"],["dc.bibliographiccitation.volume","20"],["dc.contributor.author","Drinkut, A."],["dc.contributor.author","Tereshchenko, Y."],["dc.contributor.author","Schulz, J. B."],["dc.contributor.author","Bähr, M."],["dc.contributor.author","Kügler, Sebastian"],["dc.date.accessioned","2017-09-07T11:48:58Z"],["dc.date.available","2017-09-07T11:48:58Z"],["dc.date.issued","2012"],["dc.description.abstract","Current gene therapy approaches for Parkinson's -disease (PD) deliver neurotrophic factors like glial cell line-derived neurotrophic factor (GDNF) or neurturin via neuronal transgene expression. Since these potent signaling-inducing neurotrophic factors can be distributed through long-distance neuronal projections to unaffected brain sites, this mode of delivery may eventually cause side effects. To explore a localized and thus potentially safer alternative for gene therapy of PD, we expressed GDNF exclusively in astrocytes and evaluated the efficacy of this approach in the mouse 1-methyl-4-phenyl-1,2,3, -6-tetrahydropyridine (MPTP) and rat -6-hydroxy-dopamine (6-OHDA) models of PD. In terms of protection of dopaminergic cell bodies and projections, dopamine (DA) synthesis and behaviour, -astrocyte-derived GDNF demonstrated the same efficacy as neuron-derived GDNF. In terms of safety, unilateral striatal GDNF expression in astrocytes did not result in delivery of bio-active GDNF to the contralateral hemispheres (potential off-target sites) as happened when GDNF was expressed in neurons. Thus, astrocytic GDNF expression represents a localized but efficient alternative to current gene therapeutic strategies for the treatment of PD, especially if viral vectors with enhanced tissue -penetration are considered. Astrocytic neurotrophic -factor expression may open new venues for neurotrophic factor-based gene therapy targeting severe diseases of the brain. Received 19 May 2011; accepted 18 October 2011; published online 15 November 2011. doi:10.1038/mt.2011.249"],["dc.identifier.doi","10.1038/mt.2011.249"],["dc.identifier.gro","3142573"],["dc.identifier.isi","000300943700007"],["dc.identifier.pmid","22086235"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/8589"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/8939"],["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","1525-0016"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Efficient Gene Therapy for Parkinson's Disease Using Astrocytes as Hosts for Localized Neurotrophic Factor Delivery"],["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.journal","Molecular therapy. Nucleic acids"],["dc.bibliographiccitation.volume","2"],["dc.contributor.author","Maddalena, Andrea"],["dc.contributor.author","Tereshchenko, Julia"],["dc.contributor.author","Bähr, Mathias"],["dc.contributor.author","Kügler, Sebastian"],["dc.date.accessioned","2018-02-22T10:47:35Z"],["dc.date.available","2018-02-22T10:47:35Z"],["dc.date.issued","2013"],["dc.description.abstract","Gene therapy, in its current configuration, is irreversible and does not allow control over transgene expression in case of side effects. Only few regulated vector systems are available, and none of these has reached clinical applicability yet. The mifepristone (Mfp)-regulated Gene Switch (GS) system is characterized by promising features such as being composed of mainly human components and an approved small-molecule drug as an inducer. However, it has not yet been evaluated in adeno-associated virus (AAV) vectors, neither has it been tested for applicability in viral vectors in the central nervous system (CNS). Here, we demonstrate that the GS system can be used successfully in AAV vectors in the brain, and that short-term induced glial cell line-derived neurotrophic factor (GDNF) expression prevented neurodegeneration in a rodent model of Parkinson's disease (PD). We also demonstrate repeated responsiveness to the inducer Mfp and absence of immunological tissue reactions in the rat brain. Human equivalent dosages of Mfp used in this study were lower than those used safely for treatment of psychiatric threats, indicating that the inducer could be safely applied in patients. Our results suggest that the GS system in AAV vectors is well suited for further development towards clinical applicability.Molecular Therapy-Nucleic Acids (2013) 2, e106; doi:10.1038/mtna.2013.35; published online 16 July 2013."],["dc.identifier.doi","10.1038/mtna.2013.35"],["dc.identifier.pmid","23860550"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/10496"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/12414"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","final"],["dc.relation.doi","10.1038/mtna.2013.35"],["dc.rights","CC BY-NC-ND 3.0"],["dc.rights.uri","https://creativecommons.org/licenses/by-nc-nd/3.0"],["dc.title","Adeno-associated Virus-mediated, Mifepristone-regulated Transgene Expression in the Brain"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","13"],["dc.bibliographiccitation.journal","Molecular Therapy — Nucleic Acids"],["dc.bibliographiccitation.lastpage","25"],["dc.bibliographiccitation.volume","8"],["dc.contributor.author","Taschenberger, Grit"],["dc.contributor.author","Tereshchenko, Julia"],["dc.contributor.author","Kuegler, Sebastian"],["dc.date.accessioned","2018-11-07T10:21:49Z"],["dc.date.available","2018-11-07T10:21:49Z"],["dc.date.issued","2017"],["dc.description.abstract","Experimentally restricting transgene expression exclusively to astrocytes has proven difficult. Using adeno-associated-virus-mediated gene transfer, we assessed two commonly used glial fibrillary acidic protein promoters: the full-length version gfa2 (2,210-bp human glial fibrillary acidic protein [GFAP] promoter) and the truncated variant gfaABC(1)D (681-bp GFAP promoter). The capacity to drive efficient, but also cell-type specific, expression of the EGFP in astrocytes was tested both in vitro in rat primary cortical cultures as well as in vivo in the rat striatum. We observed an efficient, but not entirely astrocyte-specific, gfa2-driven reporter expression. gfaABC(1)D exhibited a weaker activity, and most importantly, off-target, neuronal expression of the transgene occurred in a larger fraction of cells. Therefore, we explored the potential of a microRNA (miR)-specific target-sequence-based approach for abolishing off-target expression. When miR124 target sequences were incorporated into the 30' UTR, neuronal gene expression was effectively silenced. However, unexpectedly, the insertion of an additional sequence in the 3' UTR clearly diminished transgene expression. In conclusion, the gfaABC(1)D promoter on its own is not sufficient to specifically target transgene expression to astrocytes and is not well suited for AAV-based gene targeting, even if short promoter sequences are required. The combination with a miR de-targeting sequence represents a promising experimental strategy that eliminates off-target, neuronal expression."],["dc.description.sponsorship","German Research Council"],["dc.identifier.doi","10.1016/j.omtn.2017.03.009"],["dc.identifier.isi","000403537300002"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/42164"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","PUB_WoS_Import"],["dc.publisher","Cell Press"],["dc.relation.issn","2162-2531"],["dc.title","A MicroRNA124 Target Sequence Restores Astrocyte Specificity of gfaABC(1)D-Driven Transgene Expression in AAV-Mediated Gene Transfer"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","475"],["dc.bibliographiccitation.issue","4"],["dc.bibliographiccitation.journal","Acta Neuropathologica"],["dc.bibliographiccitation.lastpage","485"],["dc.bibliographiccitation.volume","121"],["dc.contributor.author","Garrido, M."],["dc.contributor.author","Tereshchenko, Y."],["dc.contributor.author","Zhevtsova, Z."],["dc.contributor.author","Taschenberger, G."],["dc.contributor.author","Bähr, M."],["dc.contributor.author","Kügler, Sebastian"],["dc.date.accessioned","2017-09-07T11:44:18Z"],["dc.date.available","2017-09-07T11:44:18Z"],["dc.date.issued","2011"],["dc.description.abstract","Parkinson's disease is a neurodegenerative disorder characterized by severe motor deficits mainly due to degeneration of dopaminergic neurons in the substantia nigra. Decreased levels of the cell's most important anti-oxidant, glutathione, have been detected in nigral neurons of Parkinson patients, but it is unknown if they are the cause or merely the consequence of the disease. To elucidate if glutathione depletion causes selective degeneration of nigral dopaminergic neurons, we down-regulated glutathione synthesis in different brain areas of adult rats by a viral vector-based RNAi approach. Decreased glutathione synthesis resulted in progressive degeneration of nigral dopaminergic neurons, while extra-nigral and striatal neurons were significantly less vulnerable. Degeneration of dopaminergic neurons was accompanied by progressive protein aggregate formation and functional motor deficits and was partially rescued by alpha-synuclein. That the survival of nigral dopaminergic neurons depends on the precise control of glutathione levels was further demonstrated by significant degeneration induced through moderate overproduction of glutathione. Over-expression of either of the two subunits of glutamate-cysteine ligase induced aberrant glutathiolation of cellular proteins and significant degeneration of dopaminergic neurons. Thus, while glutathione depletion was demonstrated to be a selective trigger for dopaminergic neuron degeneration, a glutathione replacement approach as a potential treatment option for Parkinson's patients must be considered with great care. In conclusion, our data demonstrate that survival of nigral dopaminergic neurons crucially depends on a tight regulation of their glutathione levels and that the depleted glutathione content detected in the brains of Parkinson's disease patients can be a causative insult for neuronal degeneration."],["dc.identifier.doi","10.1007/s00401-010-0791-x"],["dc.identifier.gro","3142758"],["dc.identifier.isi","000288446100004"],["dc.identifier.pmid","21191602"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/6612"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/197"],["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.eissn","1432-0533"],["dc.relation.issn","0001-6322"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Glutathione depletion and overproduction both initiate degeneration of nigral dopaminergic 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","671"],["dc.bibliographiccitation.issue","5"],["dc.bibliographiccitation.journal","Acta Neuropathologica"],["dc.bibliographiccitation.lastpage","683"],["dc.bibliographiccitation.volume","123"],["dc.contributor.author","Taschenberger, G."],["dc.contributor.author","Garrido, M."],["dc.contributor.author","Tereshchenko, Y."],["dc.contributor.author","Baehr, M."],["dc.contributor.author","Zweckstetter, M."],["dc.contributor.author","Kügler, Sebastian"],["dc.date.accessioned","2017-09-07T11:48:53Z"],["dc.date.available","2017-09-07T11:48:53Z"],["dc.date.issued","2012"],["dc.description.abstract","Fibrillar alpha Synuclein is the major constituent of Lewy bodies and Lewy neurites, the protein deposits characteristic for Parkinson's disease (PD). Multiplications of the alpha Synuclein gene, as well as point mutations cause familial PD. However, the exact role of alpha Synuclein in neurodegeneration remains uncertain. Recent research in invertebrates has suggested that oligomeric rather than fibrillizing alpha Synuclein mediates neurotoxicity. To investigate the impact of alpha Synuclein aggregation on the progression of neurodegeneration, we expressed variants with different fibrillation propensities in the rat substantia nigra (SN) by means of recombinant adeno-associated viral (AAV) vectors. The formation of proteinase K-resistant alpha Synuclein aggregates was correlated to the loss of nigral dopaminergic (DA) neurons and striatal fibers. Expression of two prefibrillar, structure-based design mutants of alpha Synuclein (i.e., A56P and A30P/A56P/A76P) resulted in less aggregate formation in nigral DA neurons as compared to human wild-type (WT) or the inherited A30P mutation. However, only the alpha Synuclein variants capable of forming fibrils (WT/A30P), but not the oligomeric alpha Synuclein species induced a sustained progressive loss of adult nigral DA neurons. These results demonstrate that divergent modes of alpha Synuclein neurotoxicity exist in invertebrate and mammalian DA neurons in vivo and suggest that fibrillation of alpha Synuclein promotes the progressive degeneration of nigral DA neurons as found in PD patients."],["dc.identifier.doi","10.1007/s00401-011-0926-8"],["dc.identifier.gro","3142543"],["dc.identifier.isi","000302255000004"],["dc.identifier.pmid","22167382"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/8092"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/8906"],["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","0001-6322"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.subject","αSynuclein; Parkinson’s disease; Aggregation; Adeno-associated virus; Substantia nigra"],["dc.title","Aggregation of αSynuclein promotes progressive in vivo neurotoxicity in adult rat dopaminergic 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","35"],["dc.bibliographiccitation.journal","Neurobiology of Disease"],["dc.bibliographiccitation.lastpage","42"],["dc.bibliographiccitation.volume","65"],["dc.contributor.author","Tereshchenko, J."],["dc.contributor.author","Maddalena, A."],["dc.contributor.author","Bähr, M."],["dc.contributor.author","Kügler, Sebastian"],["dc.date.accessioned","2017-09-07T11:46:17Z"],["dc.date.available","2017-09-07T11:46:17Z"],["dc.date.issued","2014"],["dc.description.abstract","Neurotrophic factors have raised hopes to be able to cure symptoms and to prevent progressive neurodegeneration in devastating neurological diseases. Gene therapy by means of viral vectors can overcome the hurdle of targeted delivery, but its current configuration is irreversible and thus much less controllable than that of classical pharmacotherapies. We thus aimed at developing a strategy allowing for both curative and controllable neurotrophic factor expression. Therefore, the short-term, intermittent and reversible expression of a neutrophic factor was evaluated for therapeutic efficacy in a slowly progressive animal model of Parkinson's disease (PD). We demonstrate that short-term induced expression of glial cell line derived neurotrophic factor (GDNF) is sufficient to provide i) substantial protection of nigral dopaminergic neurons from degeneration and ii) restoration of dopamine supply and motor behaviour in the partial striatal 6-OHDA model PD. These neurorestorative effects of GDNF lasted several weeks beyond the time of its expression. Later on, therapeutic efficacy ceased, but was restored by a second short induction of GDNF expression, demonstrating that monthly application of the inducing drug mifepristone was sufficient to maintain neuroprotective and neurorestorative GDNF levels. These findings suggest that forthcoming gene therapies for PD or other neurodegenerative disorders can be designed in a way that low frequency application of an approved drug can provide controllable and therapeutically efficient levels of GDNF or other neurotrophic factors. Neurotrophic factor expression can be withdrawn in case of off-target effects or sufficient clinical benefit, a feature that may eventually increase the acceptance of gene therapy for less advanced patients, which may profit better from such approaches. (C) 2014 Elsevier Inc. All rights reserved."],["dc.identifier.doi","10.1016/j.nbd.2014.01.009"],["dc.identifier.gro","3142138"],["dc.identifier.isi","000333546300004"],["dc.identifier.pmid","24440408"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/4966"],["dc.language.iso","en"],["dc.notes.intern","WoS Import 2017-03-10 / Funder: German Research Council; European Community [HEALTH-2008-222925]"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.eissn","1095-953X"],["dc.relation.issn","0969-9961"],["dc.subject","Parkinson; Gene therapy; Regulation; Neurotrophic factor; AAV vector"],["dc.title","Pharmacologically controlled, discontinuous GDNF gene therapy restores motor function in a rat model of Parkinson's disease"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","79"],["dc.bibliographiccitation.journal","Experimental Neurology"],["dc.bibliographiccitation.lastpage","90"],["dc.bibliographiccitation.volume","309"],["dc.contributor.author","Cheng, Shi"],["dc.contributor.author","Tereshchenko, Julia"],["dc.contributor.author","Zimmer, Virginie"],["dc.contributor.author","Vachey, Gabriel"],["dc.contributor.author","Pythoud, Catherine"],["dc.contributor.author","Rey, Maria"],["dc.contributor.author","Liefhebber, Jolanda"],["dc.contributor.author","Raina, Anupam"],["dc.contributor.author","Streit, Frank"],["dc.contributor.author","Mazur, Andrzej"],["dc.contributor.author","Bähr, Mathias"],["dc.contributor.author","Konstantinova, Pavlina"],["dc.contributor.author","Déglon, Nicole"],["dc.contributor.author","Kügler, Sebastian"],["dc.date.accessioned","2020-12-10T14:24:01Z"],["dc.date.available","2020-12-10T14:24:01Z"],["dc.date.issued","2018"],["dc.identifier.doi","10.1016/j.expneurol.2018.07.017"],["dc.identifier.issn","0014-4886"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/72105"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.title","Therapeutic efficacy of regulable GDNF expression for Huntington's and Parkinson's disease by a high-induction, background-free “GeneSwitch” vector"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]