References of "Glaab, Enrico 50001863"
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See detail3D Cultures of Parkinson's Disease‐Specific Dopaminergic Neurons for High Content Phenotyping and Drug Testing
Bolognin, Silvia UL; Fossépré, Marie; Qing, Xiaobing et al

in Advanced Science (2018)

Parkinson's disease (PD)‐specific neurons, grown in standard 2D cultures, typically only display weak endophenotypes. The cultivation of PD patient‐specific neurons, derived from induced pluripotent stem ... [more ▼]

Parkinson's disease (PD)‐specific neurons, grown in standard 2D cultures, typically only display weak endophenotypes. The cultivation of PD patient‐specific neurons, derived from induced pluripotent stem cells carrying the LRRK2‐G2019S mutation, is optimized in 3D microfluidics. The automated image analysis algorithms are implemented to enable pharmacophenomics in disease‐relevant conditions. In contrast to 2D cultures, this 3D approach reveals robust endophenotypes. High‐content imaging data show decreased dopaminergic differentiation and branching complexity, altered mitochondrial morphology, and increased cell death in LRRK2‐G2019S neurons compared to isogenic lines without using stressor agents. Treatment with the LRRK2 inhibitor 2 (Inh2) rescues LRRK2‐G2019S‐dependent dopaminergic phenotypes. Strikingly, a holistic analysis of all studied features shows that the genetic background of the PD patients, and not the LRRK2‐G2019S mutation, constitutes the strongest contribution to the phenotypes. These data support the use of advanced in vitro models for future patient stratification and personalized drug development. [less ▲]

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See detailCombining PET imaging and blood metabolomics data to improve machine learning models for Parkinson’s disease diagnosis
Glaab, Enrico UL; Trezzi, Jean-Pierre UL; Greuel et al

Poster (2018, October 08)

Objective: To investigate whether the integration of PET imaging and metabolomics data can provide improved machine learning models for PD diagnosis. Background: The reliable diagnosis of PD can remain ... [more ▼]

Objective: To investigate whether the integration of PET imaging and metabolomics data can provide improved machine learning models for PD diagnosis. Background: The reliable diagnosis of PD can remain challenging, even at the motor stage. PET imaging can be used to confirm the clinical diagnosis. However, limitations in the robustness of predictive features extracted from the data and the costs associated with PET imaging restrict its application. Using blood metabolomics data as an additional information source may provide improved combined diagnostic models and/or an initial filter to decide on whether to apply PET imaging. Methods: Metabolomics profiling of blood plasma samples using gas chromatography coupled to mass spectrometry (GC­MS) was conducted in 60 IPD patients and 15 healthy controls. After pre-processing, these data were compared to neuroimaging data for subsets of the same individuals using FDOPA PET (44 patients and 14 controls) and FDG PET (51 patients and 15 controls). Machine learning models using linear support vector machines were trained on 50% of the data and evaluated on a 50% hold­out test set using Receiver Operating Characteristic (ROC) curves. Next, standardized FDOPA and FDG PET intensity measurements were combined with those from the metabolomics data to build and evaluate sample classification models in the same manner as for the individual datasets. Results: Both for the FDOPA and FDG PET data, the predictive performance given by the area under the ROC curve (AUC) was highest when combining imaging features with those from the metabolomics data (AUC for FDOPA + metabolomics: 0.98; AUC for FDG + metabolomics: 0.91). The performance was generally lower when using only the respective PET attributes (FDOPA: 0.94, FDG: 0.8) or only the metabolomics data (AUC: 0.66). [less ▲]

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See detailIntegrative analysis of mitochondrial changes in Parkinson’s disease
Glaab, Enrico UL

Presentation (2018, July 16)

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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 detailComputational systems biology approaches for Parkinson's disease
Glaab, Enrico UL

in Cell and Tissue Research (2018), 373(1), 91109

Parkinson’s disease (PD) is a prime example of a complex and heterogeneous disorder, characterized by multifaceted and varied motor- and non-motor symptoms and different possible interplays of genetic and ... [more ▼]

Parkinson’s disease (PD) is a prime example of a complex and heterogeneous disorder, characterized by multifaceted and varied motor- and non-motor symptoms and different possible interplays of genetic and environmental risk factors. While investigations of individual PD-causing mutations and risk factors in isolation are providing important insights to improve our understanding of the molecular mechanisms behind PD, there is a growing consensus that a more complete understanding of these mechanisms will require an integrative modeling of multifactorial disease-associated perturbations in molecular networks. Identifying and interpreting the combinatorial effects of multiple PD-associated molecular changes may pave the way towards an earlier and reliable diagnosis and more effective therapeutic interventions. This review provides an overview of computational systems biology approaches developed in recent years to study multifactorial molecular alterations in complex disorders, with a focus on PD research applications. Strengths and weaknesses of different cellular pathway and network analyses, and multivariate machine learning techniques for investigating PD-related omics data are discussed, and strategies proposed to exploit the synergies of multiple biological knowledge and data sources. A final outlook provides an overview of specific challenges and possible next steps for translating systems biology findings in PD to new omics-based diagnostic tools and targeted, drug-based therapeutic approaches. [less ▲]

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See detailA structure-activity relationship linking non-planar PCBs to functional deficits of neural crest cells: new roles for connexins
Nyffeler, Johanna; Chovancova, Petra; Dolde, Xenia et al

in Archives of Toxicology (2018), 92(3), 12251247

Migration of neural crest cells (NCC) is a fundamental developmental process, and test methods to identify interfering toxicants have been developed. By examining cell function endpoints, as in the ... [more ▼]

Migration of neural crest cells (NCC) is a fundamental developmental process, and test methods to identify interfering toxicants have been developed. By examining cell function endpoints, as in the ‘migration-inhibition of NCC (cMINC)’ assay, a large number of toxicity mechanisms and protein targets can be covered. However, the key events that lead to the adverse effects of a given chemical or group of related compounds are hard to elucidate. To address this issue, we explored here, whether the establishment of two overlapping structure–activity relationships (SAR)—linking chemical structure on the one hand to a phenotypic test outcome, and on the other hand to a mechanistic endpoint—was useful as strategy to identify relevant toxicity mechanisms. For this purpose, we chose polychlorinated biphenyls (PCB) as a large group of related, but still toxicologically and physicochemically diverse structures. We obtained concentration-dependent data for 26 PCBs in the cMINC assay. Moreover, the test chemicals were evaluated by a new high-content imaging method for their effect on cellular re-distribution of connexin43 and for their capacity to inhibit gap junctions. Non-planar PCBs inhibited NCC migration. The potency (1–10 μM) correlated with the number of ortho-chlorine substituents; non-ortho-chloro (planar) PCBs were non-toxic. The toxicity to NCC partially correlated with gap junction inhibition, while it fully correlated (p < 0.0004) with connexin43 cellular re-distribution. Thus, our double-SAR strategy revealed a mechanistic step tightly linked to NCC toxicity of PCBs. Connexin43 patterns in NCC may be explored as a new endpoint relevant to developmental toxicity screening. [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 detailAbsence of regulator of G-protein signaling 4 does not protect against dopamine neuron dysfunction and injury in the mouse 6-hydroxydopamine lesion model of Parkinson's disease
Ashrafi, Amer UL; Garcia, Pierre UL; Kollmus, Heike et al

in Neurobiology of Aging (2017), 58

Regulator of G-Protein Signaling 4 (RGS4), a member of the RGS family of proteins that inactivate G-proteins, has gained interest as a potential drug target for neurological disorders, such as epilepsy ... [more ▼]

Regulator of G-Protein Signaling 4 (RGS4), a member of the RGS family of proteins that inactivate G-proteins, has gained interest as a potential drug target for neurological disorders, such as epilepsy and Parkinson’s disease (PD). In the case of PD, the main current option for alleviating motor symptoms are dopamine replacement therapies, which have limitations because of side effects, and reduced effectiveness over the long term. Research on new non-dopaminergic PD drug targets has indicated that inhibition of RGS4 could be an effective adjuvant treatment option. The effectiveness of RGS4 inhibition for an array of PD-linked functional and structural neuroprotection endpoints has not yet been demonstrated. Here, we use the 6-Hydroxydopamine (6-OHDA) lesioning model of the nigrostriatal pathway in mice to address this question. We observe, using a battery of behavioral and pathological measures, that mice deficient for RGS4 are not protected from 6-OHDA induced injury, and show enhanced susceptibility in some measures of motor function. Our results suggest that inhibition of RGS4 as a non-dopaminergic target for PD should be approached with caution. [less ▲]

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See detailMetformin reverses TRAP1 mutation-associated alterations in mitochondrial function in Parkinson's disease
Fitzgerald, Julia C.; Zimprich, Alexander; Carvajal-Berrio, Daniel A. et al

in Brain : A Journal of Neurology (2017), 140(9), 2444-2459

The mitochondrial proteins TRAP1 and HtrA2 have previously been shown to be phosphorylated in the presence of the Parkinson’s disease kinase PINK1 but the downstream signaling is unclear. HtrA2 and PINK1 ... [more ▼]

The mitochondrial proteins TRAP1 and HtrA2 have previously been shown to be phosphorylated in the presence of the Parkinson’s disease kinase PINK1 but the downstream signaling is unclear. HtrA2 and PINK1 loss of function causes parkinsonism in humans and animals. Here, we identified TRAP1 as an interactor of HtrA2 using an unbiased mass spectrometry approach. In our human cell models, TRAP1 overexpression is protective, rescuing HtrA2 and PINK1-associated mitochondrial dysfunction and suggesting that TRAP1 acts downstream of HtrA2 and PINK1. HtrA2 regulates TRAP1 protein levels, but TRAP1 is not a direct target of HtrA2 protease activity. Following genetic screening of Parkinson’s disease patients and healthy controls, we also report the first TRAP1 mutation leading to complete loss of functional protein in a patient with late onset Parkinson’s disease. Analysis of fibroblasts derived from the patient reveal that oxygen consumption, ATP output and reactive oxygen species are increased compared to healthy individuals. This is coupled with an increased pool of free NADH, increased mitochondrial biogenesis, triggering of the mitochondrial unfolded protein response, loss of mitochondrial membrane potential and sensitivity to mitochondrial removal and apoptosis. These data highlight the role of TRAP1 in the regulation of energy metabolism and mitochondrial quality control. Interestingly, the diabetes drug metformin reverses mutation-associated alterations on energy metabolism, mitochondrial biogenesis and restores mitochondrial membrane potential. In summary, our data show that TRAP1 acts downstream of PINK1 and HtrA2 for mitochondrial fine tuning, whereas TRAP1 loss of function leads to reduced control of energy metabolism, ultimately impacting mitochondrial membrane potential. These findings offer new insight into mitochondrial pathologies in Parkinson’s disease and provide new prospects for targeted therapies. [less ▲]

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See detailNeuroChip, an updated version of the NeuroX genotyping platform to rapidly screen for variants associated with neurological diseases
Blauwendraat, Cornelis; Faghri, Faraz; Pihlstrom, Lasse et al

in Neurobiology of Aging (2017)

Genetics has proven to be a powerful approach in neurodegenerative diseases research, resulting in the identification of numerous causal and risk variants. Previously, we introduced the NeuroX Illumina ... [more ▼]

Genetics has proven to be a powerful approach in neurodegenerative diseases research, resulting in the identification of numerous causal and risk variants. Previously, we introduced the NeuroX Illumina genotyping array, a fast and efficient genotyping platform designed for the investigation of genetic variation in neurodegenerative diseases. Here, we present its updated version, named NeuroChip. The NeuroChip is a low cost, custom-designed array containing a tagging variant backbone of about 306,670 variants complemented with a manually curated custom content comprised of 179,467 variants implicated in diverse neurological diseases, including Alzheimer’s disease, Parkinson’s disease, Lewy body dementia, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration and multiple system atrophy. The tagging backbone was chosen because of the low cost and good genome-wide resolution; the custom content can be combined with other backbones, like population or drug development arrays. Using the NeuroChip, we can accurately identify rare variants and impute over 5.3 million common SNPs from the latest release of the Haplotype Reference Consortium. In summary, we describe the design and usage of the NeuroChip array, and show its capability for detecting rare pathogenic variants in numerous neurodegenerative diseases. The NeuroChip has a more comprehensive and improved content, which makes it a reliable, high-throughput, cost-effective screening tool for genetic research and molecular diagnostics in neurodegenerative diseases. [less ▲]

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See detailBiomedical Data Science at LCSB
Glaab, Enrico UL

Presentation (2017)

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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 detailMolecular Identification of D-Ribulokinase in Budding Yeast and Mammals
Singh, Charandeep UL; Glaab, Enrico UL; Linster, Carole UL

in Journal of Biological Chemistry (2017), 292(3), 1005-1028

Proteomes of even well characterized organisms still contain a high percentage of proteins with unknown or uncertain molecular and/or biological function. A significant fraction of those proteins are ... [more ▼]

Proteomes of even well characterized organisms still contain a high percentage of proteins with unknown or uncertain molecular and/or biological function. A significant fraction of those proteins are predicted to have catalytic properties. Here we aimed at identifying the function of the Saccharomyces cerevisiae Ydr109c protein and of its human homolog FGGY, both of which belong to the broadly conserved FGGY family of carbohydrate kinases. Functionally identified members of this family phosphorylate 3- to 7-carbon sugars or sugar derivatives, but the endogenous substrate of S. cerevisiae Ydr109c and human FGGY has remained unknown. Untargeted metabolomics analysis of an S. cerevisiae deletion mutant of YDR109C revealed ribulose as one of the metabolites with the most significantly changed intracellular concentration as compared to a wild-type strain. In human HEK293 cells, ribulose could only be detected when ribitol was added to the cultivation medium and under this condition, FGGY silencing led to ribulose accumulation. Biochemical characterization of the recombinant purified Ydr109c and FGGY proteins showed a clear substrate preference of both kinases for D-ribulose over a range of other sugars and sugar derivatives tested, including L-ribulose. Detailed sequence and structural analyses of Ydr109c and FGGY as well as homologs thereof furthermore allowed the definition of a 5-residue D-ribulokinase signature motif (TCSLV). The physiological role of the herein identified eukaryotic D-ribulokinase remains unclear, but we speculate that S. cerevisiae Ydr109c and human FGGY could act as metabolite repair enzymes, serving to re-phosphorylate free D-ribulose generated by promiscuous phosphatases from D-ribulose-5-phosphate. In human cells, FGGY can additionally participate in ribitol metabolism. [less ▲]

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See detailAnalysis of protein druggability in the alpha-synuclein regulatory network
Glaab, Enrico UL

Presentation (2016, October 07)

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See detailIntegrating prior biological knowledge into omics data analysis
Glaab, Enrico UL

Presentation (2016, May 09)

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See detailModelling gender-specific regulation of tau in Alzheimer’s disease
Glaab, Enrico UL

Presentation (2016)

Public transcriptomic 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 transcriptomic 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 postmortem 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 underexpression 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 detailConversion of non-proliferating astrocytes into neurogenic neural stem cells: control by FGF2 and IFN-gamma
Kleiderman, Susanne; Gutbier, Simon; Tufekci, Kemal U. et al

in Stem Cells (2016), 34(12), 28612874

Conversion of astrocytes to neurons, via de-differentiation to neural stem cells (NSC), may be a new approach to treat neurodegenerative diseases and brain injuries. The signaling factors affecting such a ... [more ▼]

Conversion of astrocytes to neurons, via de-differentiation to neural stem cells (NSC), may be a new approach to treat neurodegenerative diseases and brain injuries. The signaling factors affecting such a cell conversion are poorly understood, and they are hard to identify in complex disease models or conventional cell cultures. To address this question, we developed a serum-free, strictly controlled culture system of pure and homogeneous ‘astrocytes generated form murine embryonic stem cells (ESC)’. These stem cell derived astrocytes (mAGES), as well as standard primary astrocytes resumed proliferation upon addition of FGF. The signaling of FGF receptor tyrosine kinase converted GFAP-positive mAGES to nestin-positive NSC. ERK phosphorylation was necessary, but not sufficient, for cell cycle re-entry, as EGF triggered no de-differentiation. The NSC obtained by de-differentiation of mAGES were similar to those obtained directly by differentiation of ESC, as evidenced by standard phenotyping, and also by transcriptome mapping, metabolic profiling, and by differentiation to neurons or astrocytes. The de-differentiation was negatively affected by inflammatory mediators, and in particular, interferon gamma (IFNγ) strongly impaired the formation of NSC from mAGES by a pathway involving phosphorylation of STAT1, but not the generation of nitric oxide. Thus, two antagonistic signaling pathways were identified here that affect fate conversion of astrocytes independent of genetic manipulation. The complex interplay of the respective signaling molecules that promote/inhibit astrocyte de-differentiation may explain why astrocytes do not readily form neural stem cells in most diseases. Increased knowledge of such factors may provide therapeutic opportunities to favor such conversions. [less ▲]

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See detailToward Omics-Based, Systems Biomedicine, and Path and Drug Discovery Methodologies for Depression-Inflammation Research
Maes; Nowak, Gabriel; Caso, Javier et al

in Molecular Neurobiology (2016), 53(5), 2927-2935

Meta-analyses confirm that depression is accompanied by signs of inflammation including increased levels of acute phase proteins, e.g., C-reactive protein, and pro-inflammatory cytokines, e.g ... [more ▼]

Meta-analyses confirm that depression is accompanied by signs of inflammation including increased levels of acute phase proteins, e.g., C-reactive protein, and pro-inflammatory cytokines, e.g., interleukin-6. Supporting the translational significance of this, a meta-analysis showed that anti-inflammatory drugs may have antidepressant effects. Here, we argue that inflammation and depression research needs to get onto a new track. Firstly, the choice of inflammatory biomarkers in depression research was often too selective and did not consider the broader pathways. Secondly, although mild inflammatory responses are present in depression, other immune-related pathways cannot be disregarded as new drug targets, e.g., activation of cell-mediated immunity, oxidative and nitrosative stress (O&NS) pathways, autoimmune responses, bacterial translocation, and activation of the toll-like receptor and neuroprogressive pathways. Thirdly, anti-inflammatory treatments are sometimes used without full understanding of their effects on the broader pathways underpinning depression. Since many of the activated immune-inflammatory pathways in depression actually confer protection against an overzealous inflammatory response, targeting these pathways may result in unpredictable and unwanted results. Furthermore, this paper discusses the required improvements in research strategy, i.e., path and drug discovery processes, omics-based techniques, and systems biomedicine methodologies. Firstly, novel methods should be employed to examine the intracellular networks that control and modulate the immune, O&NS and neuroprogressive pathways using omics-based assays, including genomics, transcriptomics, proteomics, metabolomics, epigenomics, immunoproteomics and metagenomics. Secondly, systems biomedicine analyses are essential to unravel the complex interactions between these cellular networks, pathways, and the multifactorial trigger factors and to delineate new drug targets in the cellular networks or pathways. Drug discovery processes should delineate new drugs targeting the intracellular networks and immune-related pathways. [less ▲]

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