Gotzmann, Nadine

[["dc.bibliographiccitation.firstpage","1"],["dc.bibliographiccitation.issue","35"],["dc.bibliographiccitation.journal","Acta Neuropathologica Communication"],["dc.bibliographiccitation.lastpage","20"],["dc.bibliographiccitation.volume","5"],["dc.contributor.author","Llorens, Franc"],["dc.contributor.author","Fischer, Andre"],["dc.contributor.author","Thüne, Katrin"],["dc.contributor.author","Sikorska, Beata"],["dc.contributor.author","Schmitz, Matthias"],["dc.contributor.author","Tahir, Waqas"],["dc.contributor.author","Fernández-Borges, Natalia"],["dc.contributor.author","Cramm, Maria"],["dc.contributor.author","Gotzmann, Nadine"],["dc.contributor.author","Carmona, Margarita"],["dc.contributor.author","Streichenberger, Nathalie"],["dc.contributor.author","Michel, Uwe"],["dc.contributor.author","Zafar, Saima"],["dc.contributor.author","Schuetz, Anna-Lena"],["dc.contributor.author","Rajput, Ashish"],["dc.contributor.author","Andréoletti, Olivier"],["dc.contributor.author","Bonn, Stefan"],["dc.contributor.author","Liberski, Pawel P."],["dc.contributor.author","Torres, Juan Maria"],["dc.contributor.author","Ferrer, Isidre"],["dc.contributor.author","Zerr, Inga"],["dc.date.accessioned","2018-01-09T14:57:08Z"],["dc.date.available","2018-01-09T14:57:08Z"],["dc.date.issued","2017-04-27"],["dc.description.abstract","Sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent form of human prion disease and it is characterized by the presence of neuronal loss, spongiform degeneration, chronic inflammation and the accumulation of misfolded and pathogenic prion protein (PrPSc). The molecular mechanisms underlying these alterations are largely unknown, but the presence of intracellular neuronal calcium (Ca2+) overload, a general feature in models of prion diseases, is suggested to play a key role in prion pathogenesis.Here we describe the presence of massive regulation of Ca2+ responsive genes in sCJD brain tissue, accompanied by two Ca2+-dependent processes: endoplasmic reticulum stress and the activation of the cysteine proteases Calpains 1/2. Pathogenic Calpain proteins activation in sCJD is linked to the cleavage of their cellular substrates, impaired autophagy and lysosomal damage, which is partially reversed by Calpain inhibition in a cellular prion model. Additionally, Calpain 1 treatment enhances seeding activity of PrPSc in a prion conversion assay. Neuronal lysosomal impairment caused by Calpain over activation leads to the release of the lysosomal protease Cathepsin S that in sCJD mainly localises in axons, although massive Cathepsin S overexpression is detected in microglial cells. Alterations in Ca2+ homeostasis and activation of Calpain-Cathepsin axis already occur at pre-clinical stages of the disease as detected in a humanized sCJD mouse model.Altogether our work indicates that unbalanced Calpain-Cathepsin activation is a relevant contributor to the pathogenesis of sCJD at multiple molecular levels and a potential target for therapeutic intervention."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2017"],["dc.identifier.doi","10.1186/s40478-017-0431-y"],["dc.identifier.pmid","28449707"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/14726"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/11612"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","final"],["dc.relation.eissn","2051-5960"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Altered Ca2+ homeostasis induces Calpain-Cathepsin axis activation in sporadic Creutzfeldt-Jakob disease"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","2249"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","Molecular Neurobiology"],["dc.bibliographiccitation.lastpage","2257"],["dc.bibliographiccitation.volume","55"],["dc.contributor.author","Llorens, Franc"],["dc.contributor.author","Kruse, Niels"],["dc.contributor.author","Karch, André"],["dc.contributor.author","Schmitz, Matthias"],["dc.contributor.author","Zafar, Saima"],["dc.contributor.author","Gotzmann, Nadine"],["dc.contributor.author","Sun, Ting"],["dc.contributor.author","Köchy, Silja"],["dc.contributor.author","Knipper, Tobias"],["dc.contributor.author","Cramm, Maria"],["dc.contributor.author","Golanska, Ewa"],["dc.contributor.author","Sikorska, Beata"],["dc.contributor.author","Liberski, Pawel P."],["dc.contributor.author","Sánchez-Valle, Raquel"],["dc.contributor.author","Fischer, Andre"],["dc.contributor.author","Mollenhauer, Brit"],["dc.contributor.author","Zerr, Inga"],["dc.date.accessioned","2018-04-23T11:47:18Z"],["dc.date.available","2018-04-23T11:47:18Z"],["dc.date.issued","2018"],["dc.description.abstract","The analysis of cerebrospinal fluid (CSF) biomarkers gains importance in the differential diagnosis of prion diseases. However, no single diagnostic tool or combination of them can unequivocally confirm prion disease diagnosis. Electrochemiluminescence (ECL)-based immunoassays have demonstrated to achieve high diagnostic accuracy in a variety of sample types due to their high sensitivity and dynamic range. Quantification of CSF α-synuclein (a-syn) by an in-house ECL-based ELISA assay has been recently reported as an excellent approach for the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD), the most prevalent form of human prion disease. In the present study, we validated a commercially available ECL-based a-syn ELISA platform as a diagnostic test for correct classification of sCJD cases. CSF a-syn was analysed in 203 sCJD cases with definite diagnosis and in 445 non-CJD cases. We investigated reproducibility and stability of CSF a-syn and made recommendations for its analysis in the sCJD diagnostic workup. A sensitivity of 98% and a specificity of 97% were achieved when using an optimal cut-off of 820 pg/mL a-syn. Moreover, we were able to show a negative correlation between a-syn levels and disease duration suggesting that CSF a-syn may be a good prognostic marker for sCJD patients. The present study validates the use of a-syn as a CSF biomarker of sCJD and establishes the clinical and pre-analytical parameters for its use in differential diagnosis in clinical routine. Additionally, the current test presents some advantages compared to other diagnostic approaches: it is fast, economic, requires minimal amount of CSF and a-syn levels are stable along disease progression."],["dc.identifier.doi","10.1007/s12035-017-0479-5"],["dc.identifier.gro","3142202"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/14714"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/13323"],["dc.language.iso","en"],["dc.notes.intern","lifescience updates Crossref Import"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","final"],["dc.relation.issn","0893-7648"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Validation of α-Synuclein as a CSF Biomarker for Sporadic Creutzfeldt-Jakob Disease"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.peerReviewed","no"],["dspace.entity.type","Publication"]]