Wales, Pauline

[["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","e1994"],["dc.bibliographiccitation.journal","Cell Death and Disease"],["dc.bibliographiccitation.volume","6"],["dc.contributor.author","Oliveira, Luis M. A."],["dc.contributor.author","Falomir-Lockhart, Lisandro J."],["dc.contributor.author","Botelho, Michelle Gralle"],["dc.contributor.author","Lin, K-H"],["dc.contributor.author","Wales, Pauline"],["dc.contributor.author","Koch, Jan Christoph"],["dc.contributor.author","Gerhardt, Ellen"],["dc.contributor.author","Taschenberger, Holger"],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.contributor.author","Lingor, Paul"],["dc.contributor.author","Schuele, B."],["dc.contributor.author","Arndt-Jovin, Donna J."],["dc.contributor.author","Jovin, Thomas M."],["dc.date.accessioned","2018-11-07T09:49:15Z"],["dc.date.available","2018-11-07T09:49:15Z"],["dc.date.issued","2015"],["dc.description.abstract","We have assessed the impact of alpha-synuclein overexpression on the differentiation potential and phenotypic signatures of two neural-committed induced pluripotent stem cell lines derived from a Parkinson's disease patient with a triplication of the human SNCA genomic locus. In parallel, comparative studies were performed on two control lines derived from healthy individuals and lines generated from the patient iPS-derived neuroprogenitor lines infected with a lentivirus incorporating a small hairpin RNA to knock down the SNCA mRNA. The SNCA triplication lines exhibited a reduced capacity to differentiate into dopaminergic or GABAergic neurons and decreased neurite outgrowth and lower neuronal activity compared with control cultures. This delayed maturation phenotype was confirmed by gene expression profiling, which revealed a significant reduction in mRNA for genes implicated in neuronal differentiation such as delta-like homolog 1 (DLK1), gamma-aminobutyric acid type B receptor subunit 2 (GABABR2), nuclear receptor related 1 protein (NURR1), G-protein-regulated inward-rectifier potassium channel 2 (GIRK-2) and tyrosine hydroxylase (TH). The differentiated patient cells also demonstrated increased autophagic flux when stressed with chloroquine. We conclude that a two-fold overexpression of alpha-synuclein caused by a triplication of the SNCA gene is sufficient to impair the differentiation of neuronal progenitor cells, a finding with implications for adult neurogenesis and Parkinson's disease progression, particularly in the context of bioenergetic dysfunction."],["dc.identifier.doi","10.1038/cddis.2015.318"],["dc.identifier.isi","000367155300027"],["dc.identifier.pmid","26610207"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/12755"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/35470"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Nature Publishing Group"],["dc.relation.issn","2041-4889"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Elevated alpha-synuclein caused by SNCA gene triplication impairs neuronal differentiation and maturation in Parkinson's patient-derived induced pluripotent stem cells"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e0157852"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","PLoS ONE"],["dc.bibliographiccitation.volume","11"],["dc.contributor.author","Pinho, Raquel"],["dc.contributor.author","Guedes, Leonor C."],["dc.contributor.author","Soreq, Lilach"],["dc.contributor.author","Lobo, Patricia P."],["dc.contributor.author","Mestre, Tiago"],["dc.contributor.author","Coelho, Miguel"],["dc.contributor.author","Rosa, Mario M."],["dc.contributor.author","Goncalves, Nilza"],["dc.contributor.author","Wales, Pauline"],["dc.contributor.author","Mendes, Tiago"],["dc.contributor.author","Gerhardt, Ellen"],["dc.contributor.author","Fahlbusch, Christiane"],["dc.contributor.author","Bonifati, Vincenzo"],["dc.contributor.author","Bonin, Michael"],["dc.contributor.author","Miltenberger-Miltenyi, Gabriel"],["dc.contributor.author","Borovecki, Fran"],["dc.contributor.author","Soreq, Hermona"],["dc.contributor.author","Ferreira, Joaquim J."],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.date.accessioned","2018-11-07T10:12:42Z"],["dc.date.available","2018-11-07T10:12:42Z"],["dc.date.issued","2016"],["dc.description.abstract","The prognosis of neurodegenerative disorders is clinically challenging due to the inexistence of established biomarkers for predicting disease progression. Here, we performed an exploratory cross-sectional, case-control study aimed at determining whether gene expression differences in peripheral blood may be used as a signature of Parkinson's disease (PD) progression, thereby shedding light into potential molecular mechanisms underlying disease development. We compared transcriptional profiles in the blood from 34 PD patients who developed postural instability within ten years with those of 33 patients who did not develop postural instability within this time frame. Our study identified >200 differentially expressed genes between the two groups. The expression of several of the genes identified was previously found deregulated in animal models of PD and in PD patients. Relevant genes were selected for validation by real-time PCR in a subset of patients. The genes validated were linked to nucleic acid metabolism, mitochondria, immune response and intracellular-transport. Interestingly, we also found deregulation of these genes in a dopaminergic cell model of PD, a simple paradigm that can now be used to further dissect the role of these molecular players on dopaminergic cell loss. Altogether, our study provides preliminary evidence that expression changes in specific groups of genes and pathways, detected in peripheral blood samples, may be correlated with differential PD progression. Our exploratory study suggests that peripheral gene expression profiling may prove valuable for assisting in prediction of PD prognosis, and identifies novel culprits possibly involved in dopaminergic cell death. Given the exploratory nature of our study, further investigations using independent, well-characterized cohorts will be essential in order to validate our candidates as predictors of PD prognosis and to definitively confirm the value of gene expression analysis in aiding patient stratification and therapeutic intervention."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2016"],["dc.identifier.doi","10.1371/journal.pone.0157852"],["dc.identifier.isi","000378212000048"],["dc.identifier.pmid","27322389"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/13385"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/40290"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Public Library Science"],["dc.relation.haserratum","/handle/2/102958"],["dc.relation.issn","1932-6203"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Gene Expression Differences in Peripheral Blood of Parkinson's Disease Patients with Distinct Progression Profiles"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","415"],["dc.bibliographiccitation.issue","4"],["dc.bibliographiccitation.journal","Journal of Parkinson s Disease"],["dc.bibliographiccitation.lastpage","459"],["dc.bibliographiccitation.volume","3"],["dc.contributor.author","Wales, Pauline"],["dc.contributor.author","Pinho, Raquel"],["dc.contributor.author","Lazaro, Diana F."],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.date.accessioned","2018-11-07T09:29:27Z"],["dc.date.available","2018-11-07T09:29:27Z"],["dc.date.issued","2013"],["dc.description.abstract","The pathogenesis of many neurodegenerative disorders arises in association with the misfolding and accumulation of a wide variety of proteins. Much emphasis has been placed on understanding the nature of these protein accumulations, including their composition, the process by which they are formed and the physiological impact they impose at cellular and, ultimately, organismal levels. Alpha-synuclein (ASYN) is the major component of protein inclusions known as Lewy bodies and Lewy neurites, which are the typical pathological hallmarks in disorders referred to as synucleinopathies. In addition, mutations or multiplications in the gene encoding for ASYN have also been shown to cause familial cases of PD, the most common synucleinopathy. Although the precise function of ASYN remains unclear, it appears to be involved in a vast array of cellular processes. Here, we review, in depth, a spectrum of cellular and molecular mechanisms that have been implicated in synucleinopathies. Importantly, detailed understanding of the biology/pathobiology of ASYN may enable the development of novel avenues for diagnosis and/or therapeutic intervention in synucleinopathies."],["dc.identifier.doi","10.3233/JPD-130216"],["dc.identifier.isi","000328332100001"],["dc.identifier.pmid","24270242"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/31034"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Ios Press"],["dc.relation.issn","1877-718X"],["dc.relation.issn","1877-7171"],["dc.title","Limelight on Alpha-Synuclein: Pathological and Mechanistic Implications in Neurodegeneration"],["dc.type","review"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","e0190552"],["dc.bibliographiccitation.issue","12"],["dc.bibliographiccitation.journal","PLOS ONE"],["dc.bibliographiccitation.volume","12"],["dc.contributor.author","Pinho, Raquel"],["dc.contributor.author","Guedes, Leonor C."],["dc.contributor.author","Soreq, Lilach"],["dc.contributor.author","Lobo, Patrícia P."],["dc.contributor.author","Mestre, Tiago"],["dc.contributor.author","Coelho, Miguel"],["dc.contributor.author","Rosa, Mário M."],["dc.contributor.author","Gonçalves, Nilza"],["dc.contributor.author","Wales, Pauline"],["dc.contributor.author","Mendes, Tiago"],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.date.accessioned","2022-03-01T11:44:12Z"],["dc.date.available","2022-03-01T11:44:12Z"],["dc.date.issued","2017"],["dc.identifier.doi","10.1371/journal.pone.0190552"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/102958"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-531"],["dc.relation.eissn","1932-6203"],["dc.relation.iserratumof","/handle/2/40290"],["dc.rights.uri","http://creativecommons.org/licenses/by/4.0/"],["dc.title","Correction: Gene Expression Differences in Peripheral Blood of Parkinson's Disease Patients with Distinct Progression Profiles"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.subtype","erratum_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","UNSP e0116919"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","PLoS ONE"],["dc.bibliographiccitation.volume","10"],["dc.contributor.author","Chen, Xiqun"],["dc.contributor.author","Wales, Pauline"],["dc.contributor.author","Quinti, Luisa"],["dc.contributor.author","Zuo, Fuxing"],["dc.contributor.author","Moniot, Sebastien"],["dc.contributor.author","Herisson, Fanny"],["dc.contributor.author","Rauf, Nazifa Abdul"],["dc.contributor.author","Wang, H."],["dc.contributor.author","Silverman, Richard B."],["dc.contributor.author","Ayata, Cenk"],["dc.contributor.author","Maxwell, Michelle M."],["dc.contributor.author","Steegborn, Clemens"],["dc.contributor.author","Schwarzschild, Michael A."],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.contributor.author","Kazantsev, Aleksey G."],["dc.date.accessioned","2018-11-07T10:02:03Z"],["dc.date.available","2018-11-07T10:02:03Z"],["dc.date.issued","2015"],["dc.description.abstract","Sirtuin deacetylases regulate diverse cellular pathways and influence disease processes. Our previous studies identified the brain-enriched sirtuin-2 (SIRT2) deacetylase as a potential drug target to counteract neurodegeneration. In the present study, we characterize SIRT2 inhibition activity of the brain-permeable compound AK7 and examine the efficacy of this small molecule in models of Parkinson's disease, amyotrophic lateral sclerosis and cerebral ischemia. Our results demonstrate that AK7 is neuroprotective in models of Parkinson's disease; it ameliorates alpha-synuclein toxicity in vitro and prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopamine depletion and dopaminergic neuron loss in vivo. The compound does not show beneficial effects in mouse models of amyotrophic lateral sclerosis and cerebral ischemia. These findings underscore the specificity of protective effects observed here in models of Parkinson's disease, and previously in Huntington's disease, and support the development of SIRT2 inhibitors as potential therapeutics for the two neurodegenerative diseases."],["dc.identifier.doi","10.1371/journal.pone.0116919"],["dc.identifier.isi","000348205300044"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/11628"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/38152"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Public Library Science"],["dc.relation.issn","1932-6203"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","The Sirtuin-2 Inhibitor AK7 Is Neuroprotective in Models of Parkinson's Disease but Not Amyotrophic Lateral Sclerosis and Cerebral Ischemia"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","2231"],["dc.bibliographiccitation.issue","12"],["dc.bibliographiccitation.journal","Human Molecular Genetics"],["dc.bibliographiccitation.lastpage","2246"],["dc.bibliographiccitation.volume","26"],["dc.contributor.author","Paiva, Isabel"],["dc.contributor.author","Pinho, Raquel"],["dc.contributor.author","Pavlou, Maria Angeliki"],["dc.contributor.author","Hennion, Magali"],["dc.contributor.author","Wales, Pauline"],["dc.contributor.author","Schütz, Anna-Lena"],["dc.contributor.author","Rajput, Ashish"],["dc.contributor.author","Szegő, Éva M."],["dc.contributor.author","Kerimoglu, Cemil"],["dc.contributor.author","Gerhardt, Ellen"],["dc.contributor.author","Rego, Ana Cristina"],["dc.contributor.author","Fischer, André"],["dc.contributor.author","Bonn, Stefan"],["dc.contributor.author","Outeiro, Tiago F."],["dc.date.accessioned","2018-04-23T11:47:17Z"],["dc.date.available","2018-04-23T11:47:17Z"],["dc.date.issued","2017"],["dc.description.abstract","Alpha-synuclein (aSyn) is considered a major culprit in Parkinson’s disease (PD) pathophysiology. However, the precise molecular function of the protein remains elusive. Recent evidence suggests that aSyn may play a role on transcription regulation, possibly by modulating the acetylation status of histones. Our study aimed at evaluating the impact of wild-type (WT) and mutant A30P aSyn on gene expression, in a dopaminergic neuronal cell model, and decipher potential mechanisms underlying aSyn-mediated transcriptional deregulation. We performed gene expression analysis using RNA-sequencing in Lund Human Mesencephalic (LUHMES) cells expressing endogenous (control) or increased levels of WT or A30P aSyn. Compared to control cells, cells expressing both aSyn variants exhibited robust changes in the expression of several genes, including downregulation of major genes involved in DNA repair. WT aSyn, unlike A30P aSyn, promoted DNA damage and increased levels of phosphorylated p53. In dopaminergic neuronal cells, increased aSyn expression led to reduced levels of acetylated histone 3. Importantly, treatment with sodium butyrate, a histone deacetylase inhibitor (HDACi), rescued WT aSyn-induced DNA damage, possibly via upregulation of genes involved in DNA repair. Overall, our findings provide novel and compelling insight into the mechanisms associated with aSyn neurotoxicity in dopaminergic cells, which could be ameliorated with an HDACi. Future studies will be crucial to further validate these findings and to define novel possible targets for intervention in PD."],["dc.identifier.doi","10.1093/hmg/ddx114"],["dc.identifier.gro","3142201"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/13321"],["dc.language.iso","en"],["dc.notes.intern","lifescience updates Crossref Import"],["dc.notes.status","final"],["dc.relation.issn","0964-6906"],["dc.title","Sodium butyrate rescues dopaminergic cells from alpha-synuclein-induced transcriptional deregulation and DNA damage"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.peerReviewed","no"],["dspace.entity.type","Publication"]]