References of "Köglsberger, Sandra 50002117"
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See detailA rare loss-of function variant of ADAM17 is associated with late-onset familial Alzheimer disease
Hartl, Daniela; May, Patrick UL; Gu, Wei UL et al

in Molecular Psychiatry (2018)

Common variants of about 20 genes contributing to AD risk have so far been identified through genome-wide association studies (GWAS). However, there is still a large proportion of heritability that might ... [more ▼]

Common variants of about 20 genes contributing to AD risk have so far been identified through genome-wide association studies (GWAS). However, there is still a large proportion of heritability that might be explained by rare but functionally important variants. One of the so far identified genes with rare AD causing variants is ADAM10. Using whole-genome sequencing we now identified a single rare nonsynonymous variant (SNV) rs142946965 [p.R215I] in ADAM17 co-segregating with an autosomal-dominant pattern of late-onset AD in one family. Subsequent genotyping and analysis of available whole-exome sequencing data of additional case/control samples from Germany, the UK and the USA identified five variant carriers among AD patients only. The mutation inhibits pro-protein cleavage and the formation of the active enzyme, thus leading to loss-of-function of ADAM17 α-secretase. Further, we identified a strong negative correlation between ADAM17 and APP gene expression in human brain and present in vitro evidence that ADAM17 negatively controls the expression of APP. As a consequence, p.R215I mutation of ADAM17 leads to elevated Aß formation in vitro. Together our data supports a causative association of the identified ADAM17 variant in the pathogenesis of AD. [less ▲]

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See detailGender-specific expression of ubiquitin-specific peptidase 9 modulates tau expression and phosphorylation: possible implications for tauopathies
Köglsberger, Sandra UL; Cordero Maldonado, Maria Lorena UL; Antony, Paul UL et al

in Molecular Neurobiology (2017), 54(10), 79797993

Public transcriptomics studies have shown that several genes display pronounced gender differences in their expression in the human brain, which may influence the manifestations and risk for neuronal ... [more ▼]

Public transcriptomics studies have shown that several genes display pronounced gender differences in their expression in the human brain, which may influence the manifestations and risk for neuronal disorders. Here we apply a transcriptome-wide analysis to discover genes with gender-specific expression and significant alterations in public post mortem brain tissue from Alzheimer’s disease (AD) patients compared to controls. We identify the sex-linked ubiquitin specific peptidase 9 (USP9) as an outstanding candidate gene with highly significant expression differences between the genders and male-specific under-expression in AD. Since previous studies have shown that USP9 can modulate the phosphorylation of the AD-associated protein MAPT, we investigate functional associations between USP9 and MAPT in further detail. After observing a high positive correlation between the expression of USP9 and MAPT in the public transcriptomics data, we show that USP9 knockdown results in significantly decreased MAPT expression in a DU145 cell culture model and a concentration-dependent decrease for the MAPT orthologs mapta and maptb in a zebrafish model. From the analysis of microarray and qRT-PCR experiments for the knockdown in DU145 cells and prior knowledge from the literature, we derive a data-congruent model for a USP9-dependent regulatory mechanism modulating MAPT expression via BACH1 and SMAD4. Overall, the analyses suggest USP9 may contribute to molecular gender differences observed in tauopathies and provide a new target for intervention strategies to modulate MAPT expression. [less ▲]

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See detailIDENTIFICATION OF A RARE GENE VARIANT THAT IS ASSOCIATED WITH FAMILIAL ALZHEIMER DISEASE AND REGULATES APP EXPRESSION
Hartl, Daniela; May, Patrick UL; Gu, Wei UL et al

in Alzheimer's & Dementia : The Journal of the Alzheimer's Association (2017), 13(7, Supplement), 648

Background Genetic mutations leading to familial forms of Alzheimer disease (AD) have so far been reported for a few genes including APP, PSEN1 and PSEN2, UNC5C, PLD3, ABCA7, TTC3, and possibly ADAM10 ... [more ▼]

Background Genetic mutations leading to familial forms of Alzheimer disease (AD) have so far been reported for a few genes including APP, PSEN1 and PSEN2, UNC5C, PLD3, ABCA7, TTC3, and possibly ADAM10. With the advent of whole exome and whole genome sequencing approaches new genes and mutations are likely to be identified. Methods We analyzed the genetic cause of AD in a large multiplex family with an autosomal-dominant pattern of inheritance with LOAD. The family lacked pathogenic mutations of known AD genes. We performed whole-genome sequencing (WGS) in six family members (two affected and four unaffected) and prioritized rare, potential damaging, variants that segregated with disease. Variants were further characterized by subsequent molecular analyzes in human brain and cell culture models. Results We identified a single rare nonsynonymous variant co-segregating with AD. The mutation inhibits pro-protein cleavage and the formation of the active enzyme, thus leading to a loss-of-function of the gene. We further found a strong negative correlation between the identified gene and APP gene expression in human brain and in cells over-expressing the gene. The negative regulation of APP expression was only observed for the wt gene, but not for mutated forms, thus causing beside the loss of enzyme function a decoupling of both APPexpression and subsequent beta-amyloid formation. The identity of the gene will be presented on the conference. Conclusions This novel pathway strongly supports a causative association of the identified gene with the pathogenesis of AD. [less ▲]

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See detailCharacterization of Differentiated SH-SY5Y as Neuronal Screening Model Reveals Increased Oxidative Vulnerability
Antony, Paul UL; Forster, Julia UL; Köglsberger, Sandra UL et al

in Journal of Biomolecular Screening : The Official Journal of the Society for Biomolecular Screening (2016)

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See detailThe Mouse Brain Metabolome: Region-Specific Signatures and Response to Excitotoxic Neuronal Injury
Jäger, Christian UL; Glaab, Enrico UL; Michelucci, Alessandro UL et al

in American Journal of Pathology (2015), 185(6), 1699-1712

Neurodegeneration is a multistep process characterized by a multitude of molecular entities and their interactions. Systems' analyses, or omics approaches, have become an important tool in characterizing ... [more ▼]

Neurodegeneration is a multistep process characterized by a multitude of molecular entities and their interactions. Systems' analyses, or omics approaches, have become an important tool in characterizing this process. Although RNA and protein profiling made their entry into this field a couple of decades ago, metabolite profiling is a more recent addition. The metabolome represents a large part or all metabolites in a tissue, and gives a snapshot of its physiology. By using gas chromatography coupled to mass spectrometry, we analyzed the metabolic profile of brain regions of the mouse, and found that each region is characterized by its own metabolic signature. We then analyzed the metabolic profile of the mouse brain after excitotoxic injury, a mechanism of neurodegeneration implicated in numerous neurological diseases. More important, we validated our findings by measuring, histologically and molecularly, actual neurodegeneration and glial response. We found that a specific global metabolic signature, best revealed by machine learning algorithms, rather than individual metabolites, was the most robust correlate of neuronal injury and the accompanying gliosis, and this signature could serve as a global biomarker for neurodegeneration. We also observed that brain lesioning induced several metabolites with neuroprotective properties. Our results deepen the understanding of metabolic changes accompanying neurodegeneration in disease models, and could help rapidly evaluate these changes in preclinical drug studies. [less ▲]

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See detailSystems genomics evaluation of the SH-SY5Y neuroblastoma cell line as a model for Parkinson’s disease
Krishna, Abhimanyu UL; Biryukov, Maria UL; Trefois, Christophe UL et al

in BMC Genomics (2014), 15(1154),

Background: The human neuroblastoma cell line, SH-SY5Y, is a commonly used cell line in studies related to neurotoxicity, oxidative stress, and neurodegenerative diseases. Although this cell line is often ... [more ▼]

Background: The human neuroblastoma cell line, SH-SY5Y, is a commonly used cell line in studies related to neurotoxicity, oxidative stress, and neurodegenerative diseases. Although this cell line is often used as a cellular model for Parkinson’s disease, the relevance of this cellular model in the context of Parkinson’s disease (PD) and other neurodegenerative diseases has not yet been systematically evaluated. Results: We have used a systems genomics approach to characterize the SH-SY5Y cell line using whole-genome sequencing to determine the genetic content of the cell line and used transcriptomics and proteomics data to determine molecular correlations. Further, we integrated genomic variants using a network analysis approach to evaluate the suitability of the SH-SY5Y cell line for perturbation experiments in the context of neurodegenerative diseases, including PD. Conclusions: The systems genomics approach showed consistency across different biological levels (DNA, RNA and protein concentrations). Most of the genes belonging to the major Parkinson’s disease pathways and modules were intact in the SH-SY5Y genome. Specifically, each analysed gene related to PD has at least one intact copy in SH-SY5Y. The disease-specific network analysis approach ranked the genetic integrity of SH-SY5Y as higher for PD than for Alzheimer’s disease but lower than for Huntington’s disease and Amyotrophic Lateral Sclerosis for loss of function perturbation experiments. [less ▲]

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See detailDifferentiated SH-SY5Y Cells as PD Model for Mitochondrial Dysfunction: From Whole Genome Sequencing to an Educated Design of High-Throughput Experiments
Antony, Paul UL; Krishna, Abhimanyu UL; May, Patrick UL et al

Poster (2013)

Objectives: Mitochondrial dysfunction is a cellular hallmark of Parkinson's disease (PD) and energetic stress of dopaminergic neurons appears to be a physiological risk factor for mitochondrial ... [more ▼]

Objectives: Mitochondrial dysfunction is a cellular hallmark of Parkinson's disease (PD) and energetic stress of dopaminergic neurons appears to be a physiological risk factor for mitochondrial dysfunction. It is however challenging to assess the high variety of factors regulating mitochondrial physiology in living neurons in a high throughput manner. To overcome this bottleneck, we established an analysis platform, using the neuroblastoma cell line SH-SY5Y. For the first time ever we have characterized the SH-SY5Y cell line in an integrated whole genome, transcriptome, and proteome approach. In addition, we show that neuronal differentiation improves the physiological properties of this experimental model for studying mitochondrial dysfunction in PD. Methods: Whole genome sequencing, RNA-Seq, qRT-PCR, MS, FRET using Voltage sensing proteins, Immunofluorescence, cytometry, and live cell imaging. Results: The integrated molecular characterization of SH-SY5Y uncovers the level of molecular network integrity and hence the relevance of this cell line for targeted studies in selected molecular processes. Furthermore, we dissect changes in mitochondrial and energetic stress factors during the process of neuronal differentiation. Conclusions: In terms of both morphology and energetic stress response, differentiated SH-SY5Y cells are more similar to dopaminergic neurons than their undifferentiated precursors. Thanks to dividing progenitors and the short duration of differentiation, combined with the use of specific endpoints analysed with high-content microscopy, our platform paves the route for high throughput experiments on a neuronal cell culture model for PD. Our genomic characterization and expression profiling of SH-SY5Y cells furthermore helps guiding the experimental design and interpretation of such studies. [less ▲]

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See detailAnalysis of critical transitions in Parkinson's disease
Trefois, Christophe UL; Antony, Paul UL; Baumuratov, Aidos UL et al

Poster (2011, December 12)

Background Parkinson’s disease is the most common neurodegenerative movement disorder and is clinically characterized by resting tremor, bradykinesia and cogwheel rigidity. The disease affects 1-2% of the ... [more ▼]

Background Parkinson’s disease is the most common neurodegenerative movement disorder and is clinically characterized by resting tremor, bradykinesia and cogwheel rigidity. The disease affects 1-2% of the global population with prevalence in the people above 65 years of age. The main pathological hallmark of Parkinson’s disease is a progressive loss of dopaminergic neurons in the substantia nigra. Therefore, one important challenge is to improve the understanding of regime shifts between health and disease states. Improving predictions of critical transitions triggering the onset of parkinsonian phenotypes could contribute to the improvement of preventive treatments. Methods Based on cellular models, we will use the mathematical concept of critical transitions to create a toolbox for potentially predicting tipping points towards cellular Parkinson’s disease phenotypes, e.g. mitochondrial dysfunction. Experimentally, we will induce and analyze potential critical transitions in the SH-SY5Y cell line. To do this, we will apply Parkinson’s disease relevant chemical and genetic perturbations and analyze multiple scales of the resulting temporal system behavior. We will combine high content imaging with genetic and biochemical data. A significant informatics challenge arises from the aim to perform the analysis of high time-resolved 3D imaging data. We are therefore developing an automated image analysis pipeline that relies on latest technologies and techniques, such as 3D deconvolution and 3D particle tracking. This pipeline will be applied to study parameters, such as mitochondrial dynamics, which include for instance velocity, morphology, and spatial organization. [less ▲]

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